DNA repair — MCQs
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A software engineer presents to the OPD with 'complaints of easy fatigability. He reports sitting in front of a computer for 12-14 hours a day consuming junk food, and eating few fruits and vegetables. CBC results show hemoglobin (Hb) concentration of $7 \mathrm{gm} \%$ and MCV of 120 fL . What is the most likely cause of anemia?
An investigator isolates bacteria from a patient who presented with dysuria and urinary frequency. These bacteria grow rapidly in pink colonies on MacConkey agar. During replication of these bacteria, the DNA strands are unwound at the origin of replication, forming two Y-shaped replication forks that open in opposite directions. At each replication fork, daughter strands are synthesized from the template strands in a 5′ to 3′ direction. On one strand, the DNA is synthesized continuously; on the other strand, the DNA is synthesized in short segments. The investigator finds that three enzymes are directly involved in elongating the DNA of the lagging strand in these bacteria. One of these enzymes has an additional function that the others do not possess. Which of the following steps in DNA replication is unique to this enzyme?
An investigator is studying the replication of bacterial DNA with modified nucleotides. After unwinding, the double-stranded DNA forms a Y-shaped replication fork that separates into two strands. At each of these strands, daughter strands are synthesized. One strand is continuously extended from the template strands in a 5′ to 3′ direction. Which of the following is exclusively associated with the strand being synthesized away from the replication fork?
While performing a Western blot, a graduate student spilled a small amount of the radiolabeled antibody on her left forearm. Although very little harm was done to the skin, the radiation did cause minor damage to the DNA of the exposed skin by severing covalent bonds between the nitrogenous bases and the deoxyribose sugar, leaving several apurinic/apyrimidinic sites. Damaged cells would most likely repair these sites by which of the following mechanisms?
A 54-year-old woman with breast cancer comes to the physician because of redness and pain in the right breast. She has been undergoing ionizing radiation therapy daily for the past 2 weeks as adjuvant treatment for her breast cancer. Physical examination shows erythema, edema, and superficial desquamation of the skin along the right breast at the site of radiation. Sensation to light touch is intact. Which of the following is the primary mechanism of DNA repair responsible for preventing radiation-induced damage to neighboring neurons?
As part of a clinical research study, the characteristics of neoplastic and normal cells are being analyzed in culture. It is observed that neoplastic cell division is aided by an enzyme which repairs progressive chromosomal shortening, which is not the case in normal cells. Due to the lack of chromosomal shortening, these neoplastic cells divide more rapidly than the normal cells. Which of the following enzymes is most likely involved?
An investigator studying DNA mutation mechanisms isolates single-stranded DNA from a recombinant bacteriophage and sequences it. The investigator then mixes it with a buffer solution and incubates the resulting mixture at 70°C for 16 hours. Subsequent DNA resequencing shows that 3.7 per 1,000 cytosine residues have mutated to uracil. Which of the following best describes the role of the enzyme that is responsible for the initial step in repairing these types of mutations in living cells?
A 47-year-old man presents to his primary care physician for fatigue. Over the past 3 months, his tiredness has impacted his ability to work as a corporate lawyer. He denies any changes to his diet, exercise regimen, bowel movements, or urinary frequency. His past medical history is notable for obesity, type II diabetes mellitus, and hypertension. He takes metformin and enalapril. His family history is notable for colorectal cancer in his father and paternal grandfather and endometrial cancer in his paternal aunt. He has a 20-pack-year smoking history and drinks one 6-pack of beer a week. His temperature is 98.8°F (37.1°C), blood pressure is 129/71 mmHg, pulse is 82/min, and respirations are 17/min. On exam, he has conjunctival pallor. A stool sample is positive for occult blood. A colonoscopy reveals a small hemorrhagic mass at the junction of the ascending and transverse colon. Which of the following processes is likely impaired in this patient?
An investigator is comparing DNA replication in prokaryotes and eukaryotes. He finds that the entire genome of E. coli (4 × 106 base pairs) is replicated in approximately 30 minutes. A mammalian genome (3 × 109 base pairs) is usually replicated within 3 hours. Which of the following characteristics of eukaryotic DNA replication is the most accurate explanation for this finding?
A 19-year-old man presents to his primary care physician for evaluation before going off to college. Specifically, he wants to know how to stay healthy while living outside his home. Since childhood he has suffered severe sunburns even when he goes outside for a small period of time. He has also developed many freckles and rough-surfaced growths starting at the same age. Finally, his eyes are very sensitive and become irritated, bloodshot, and painful after being outside. A defect in a protein with which of the following functions is most likely responsible for this patient's symptoms?
DNA repair US Medical PG Practice Questions and MCQs
Question 1: A software engineer presents to the OPD with 'complaints of easy fatigability. He reports sitting in front of a computer for 12-14 hours a day consuming junk food, and eating few fruits and vegetables. CBC results show hemoglobin (Hb) concentration of $7 \mathrm{gm} \%$ and MCV of 120 fL . What is the most likely cause of anemia?
- A. Cyanocobalamin deficiency
- B. Acute blood loss
- C. Sideroblastic anemia
- D. Folate deficiency (Correct Answer)
- E. Iron deficiency anemia
Explanation: ***Folate deficiency*** - A **macrocytic anemia** with an **MCV of 120 fL** is characteristic of folate deficiency, as folate is vital for **DNA synthesis** in red blood cell production. - The patient's diet of **junk food** and few fruits/vegetables suggests poor nutritional intake, as folate is abundant in leafy greens and fresh produce. *Cyanocobalamin deficiency* - While also causing **macrocytic anemia** with high MCV, cyanocobalamin (Vitamin B12) deficiency often presents with **neurological symptoms** (e.g., neuropathy, cognitive changes) which are not mentioned. - Dietary sources of B12 are primarily **animal products**, and while junk food is poor, a strict vegetarian/vegan diet is a stronger indicator of B12 deficiency. *Acute blood loss* - Acute blood loss typically causes **normocytic, normochromic anemia**, characterized by a normal MCV in the initial stages. - While severe blood loss can lead to fatigue, the **elevated MCV** of 120 fL makes this diagnosis unlikely unless there's a pre-existing macrocytic condition. *Sideroblastic anemia* - Sideroblastic anemia can be **microcytic, normocytic, or macrocytic**, but it is primarily characterized by the presence of **ring sideroblasts** in the bone marrow and iron overload. - It's often associated with **alcoholism, lead poisoning, or myelodysplastic syndromes**, and the typical features of the patient's diet and MCV do not point towards this condition. *Iron deficiency anemia* - Iron deficiency anemia presents with **microcytic, hypochromic anemia** with a **low MCV** (typically <80 fL), not macrocytic anemia. - While iron deficiency is the most common cause of anemia worldwide and can result from poor diet, the **elevated MCV of 120 fL** clearly excludes this diagnosis.
Question 2: An investigator isolates bacteria from a patient who presented with dysuria and urinary frequency. These bacteria grow rapidly in pink colonies on MacConkey agar. During replication of these bacteria, the DNA strands are unwound at the origin of replication, forming two Y-shaped replication forks that open in opposite directions. At each replication fork, daughter strands are synthesized from the template strands in a 5′ to 3′ direction. On one strand, the DNA is synthesized continuously; on the other strand, the DNA is synthesized in short segments. The investigator finds that three enzymes are directly involved in elongating the DNA of the lagging strand in these bacteria. One of these enzymes has an additional function that the others do not possess. Which of the following steps in DNA replication is unique to this enzyme?
- A. Elongation of lagging strand in 5'→3' direction
- B. Excision of nucleotides with 5'→3' exonuclease activity (Correct Answer)
- C. Prevention of reannealing of the leading strand and the lagging strand
- D. Creation of ribonucleotide primers
- E. Proofreading for mismatched nucleotides
Explanation: ***Excision of nucleotides with 5'→3' exonuclease activity*** - **DNA polymerase I** possesses unique **5'→3' exonuclease activity** that allows it to remove RNA primers synthesized by primase. - After primer removal, DNA polymerase I synthesizes DNA in the 5'→3' direction to fill the gap. *Elongation of lagging strand in 5'→3' direction* - While **DNA polymerase I** elongates the lagging strand, this 5'→3' synthesis function is also shared by **DNA polymerase III**, which is the primary enzyme for DNA synthesis. - Therefore, this specific function is not unique to the enzyme in question (DNA polymerase I) as DNA polymerase III also performs 5'→3' elongation. *Prevention of reannealing of the leading strand and the lagging strand* - This function is carried out by **single-strand binding proteins (SSBs)**, which bind to the separated DNA strands to prevent them from reannealing and protect them from degradation. - This is not a function of any DNA polymerase. *Creation of ribonucleotide primers* - The synthesis of short RNA primers required for initiation of DNA synthesis is performed by **primase**, an RNA polymerase. - DNA polymerases do not create primers but rather extend them. *Proofreading for mismatched nucleotides* - **DNA polymerase I** and **DNA polymerase III** both possess **3'→5' exonuclease activity** for proofreading, allowing them to remove incorrectly incorporated nucleotides. - Since this function is shared by DNA polymerase III, it is not unique to DNA polymerase I.
Question 3: An investigator is studying the replication of bacterial DNA with modified nucleotides. After unwinding, the double-stranded DNA forms a Y-shaped replication fork that separates into two strands. At each of these strands, daughter strands are synthesized. One strand is continuously extended from the template strands in a 5′ to 3′ direction. Which of the following is exclusively associated with the strand being synthesized away from the replication fork?
- A. Reverse transcriptase activity
- B. Repeated activity of ligase (Correct Answer)
- C. Elongation in the 3'→5' direction
- D. Synthesis of short RNA sequences
- E. 5' → 3' exonuclease activity
Explanation: ***Repeated activity of ligase*** - The lagging strand, synthesized away from the replication fork, is made in fragments (**Okazaki fragments**) due to the 5' to 3' synthesis direction of DNA polymerase. - **DNA ligase** repeatedly joins these Okazaki fragments together, forming a continuous strand. *Reverse transcriptase activity* - **Reverse transcriptase** synthesizes DNA from an RNA template, which is not involved in normal bacterial DNA replication. - This enzyme is characteristic of **retroviruses** and certain eukaryotic telomere maintenance. *Elongation in the 3'→5' direction* - DNA polymerases only synthesize new DNA strands in the **5' to 3' direction**. - While reading the template strand in the 3' to 5' direction, the daughter strand is always built from 5' to 3'. *Synthesis of short RNA sequences* - **RNA primers** are synthesized by **primase** on both the leading and lagging strands to initiate DNA synthesis. - This process is not exclusive to the strand synthesized away from the replication fork; the leading strand also requires an initial RNA primer. *5' → 3' exonuclease activity* - The **5' to 3' exonuclease activity** of DNA polymerase I in bacteria is responsible for removing RNA primers. - This activity occurs on both the leading and lagging strands, as both require primer removal.
Question 4: While performing a Western blot, a graduate student spilled a small amount of the radiolabeled antibody on her left forearm. Although very little harm was done to the skin, the radiation did cause minor damage to the DNA of the exposed skin by severing covalent bonds between the nitrogenous bases and the deoxyribose sugar, leaving several apurinic/apyrimidinic sites. Damaged cells would most likely repair these sites by which of the following mechanisms?
- A. Nucleotide excision repair
- B. Nonhomologous end joining repair
- C. Homologous recombination
- D. Mismatch repair
- E. Base excision repair (Correct Answer)
Explanation: **Base excision repair** - This mechanism is specifically involved in correcting **single-base DNA damage** or **modified bases**, such as **apurinic/apyrimidinic (AP) sites**. - It involves removing the damaged base by a **DNA glycosylase**, creating an AP site, which is then processed by an **AP endonuclease** to cleave the phosphodiester backbone, followed by DNA polymerase and ligase. *Nucleotide excision repair* - Primarily repairs **bulky DNA lesions**, such as **thymine dimers** caused by UV radiation, or damage from chemical adducts that distort the DNA helix. - It involves excising a larger oligonucleotide containing the damage, not just a single base. *Nonhomologous end joining repair* - This pathway is used to repair **double-strand DNA breaks**, where both strands of the DNA molecule are broken. - It is a "quick-and-dirty" repair mechanism that ligates the broken ends together, often leading to small insertions or deletions. *Homologous recombination* - A repair mechanism for **double-strand DNA breaks** that uses a homologous DNA template (e.g., sister chromatid) to accurately repair the break. - This process is highly accurate but occurs only when a homologous template is available, typically during the S and G2 phases of the cell cycle. *Mismatch repair* - Corrects **base-pair mismatches** and **small insertions/deletions** that occur during DNA replication, which were not corrected by DNA polymerase proofreading. - It targets newly synthesized DNA strands based on methylation patterns in the parental strand.
Question 5: A 54-year-old woman with breast cancer comes to the physician because of redness and pain in the right breast. She has been undergoing ionizing radiation therapy daily for the past 2 weeks as adjuvant treatment for her breast cancer. Physical examination shows erythema, edema, and superficial desquamation of the skin along the right breast at the site of radiation. Sensation to light touch is intact. Which of the following is the primary mechanism of DNA repair responsible for preventing radiation-induced damage to neighboring neurons?
- A. Homology-directed repair
- B. Base excision repair
- C. Nonhomologous end joining repair (Correct Answer)
- D. DNA mismatch repair
- E. Nucleotide excision repair
Explanation: ***Nonhomologous end joining repair*** - This pathway is crucial for repairing **double-strand DNA breaks**, which are a major form of damage caused by **ionizing radiation**. - It directly ligates the broken DNA ends without requiring a homologous template, making it an efficient but potentially error-prone repair mechanism. *Homology-directed repair* - This pathway is also used to repair **double-strand DNA breaks** but requires a **homologous DNA template** (usually a sister chromatid) for accurate repair. - While highly accurate, it is typically active during the S and G2 phases of the cell cycle and is generally slower and less dominant than NHEJ for immediate radiation-induced damage in non-dividing cells like neurons. *Base excision repair* - This mechanism primarily corrects damage to individual DNA bases, such as **oxidative damage**, alkylation, or deamination. - It is not the primary mechanism for repairing the **double-strand breaks** induced by ionizing radiation. *DNA mismatch repair* - This pathway corrects errors that arise during **DNA replication**, specifically mismatched base pairs or small insertions/deletions. - It is not involved in repairing radiation-induced DNA damage like **double-strand breaks**. *Nucleotide excision repair* - This pathway repairs bulky DNA lesions, such as those caused by **UV radiation** (e.g., pyrimidine dimers) or chemical mutagens. - It removes a segment of DNA containing the damage but is not the primary repair mechanism for **double-strand breaks** caused by ionizing radiation.
Question 6: As part of a clinical research study, the characteristics of neoplastic and normal cells are being analyzed in culture. It is observed that neoplastic cell division is aided by an enzyme which repairs progressive chromosomal shortening, which is not the case in normal cells. Due to the lack of chromosomal shortening, these neoplastic cells divide more rapidly than the normal cells. Which of the following enzymes is most likely involved?
- A. Topoisomerase
- B. DNA polymerase
- C. Reverse transcriptase
- D. Protein kinase
- E. Telomerase (Correct Answer)
Explanation: ***Telomerase*** - **Telomerase** is an enzyme that adds repetitive nucleotide sequences (telomeres) to the ends of chromosomes, counteracting their progressive shortening during DNA replication. This activity is crucial for the continuous division of neoplastic cells. - In normal somatic cells, **telomerase activity is typically low or absent**, leading to telomere shortening with each division, eventually triggering cellular senescence or apoptosis. The presence of telomerase in neoplastic cells allows them to bypass these natural limits on proliferation. *Topoisomerase* - **Topoisomerases** are enzymes that regulate the supercoiling of DNA by breaking and rejoining DNA strands, which is essential during replication and transcription to relieve torsional stress. - They do not directly repair chromosomal shortening but rather manage the topological state of DNA. *DNA polymerase* - **DNA polymerase** is primarily responsible for synthesizing new DNA strands by adding nucleotides, thereby elongating the DNA molecule during replication and DNA repair processes. - While essential for DNA replication, it cannot fully replicate the very ends of linear chromosomes, leading to the **end-replication problem** and telomere shortening. *Reverse transcriptase* - **Reverse transcriptase** is an enzyme that synthesizes DNA from an RNA template, a process central to retroviruses and some eukaryotic elements like retrotransposons. - Although telomerase itself is a specialized reverse transcriptase (using an RNA template to synthesize DNA telomeres), the general term "reverse transcriptase" does not specifically refer to the enzyme that repairs chromosomal shortening in the context of cell division. *Protein kinase* - **Protein kinases** are enzymes that add phosphate groups to proteins, a process known as phosphorylation. This modification can alter protein activity, localization, or stability, playing a critical role in signal transduction pathways. - They are involved in regulating various cellular processes, including cell growth and division, but do not directly repair chromosomal shortening.
Question 7: An investigator studying DNA mutation mechanisms isolates single-stranded DNA from a recombinant bacteriophage and sequences it. The investigator then mixes it with a buffer solution and incubates the resulting mixture at 70°C for 16 hours. Subsequent DNA resequencing shows that 3.7 per 1,000 cytosine residues have mutated to uracil. Which of the following best describes the role of the enzyme that is responsible for the initial step in repairing these types of mutations in living cells?
- A. Connecting the phosphodiester backbone
- B. Cleavage of the phosphodiester bond 3' of damaged site
- C. Creation of abasic site (Correct Answer)
- D. Release of the damaged nucleotide
- E. Addition of free nucleotides to 3' end
Explanation: ***Creation of abasic site*** - The mutation of **cytosine to uracil** is an example of **deamination**, which is repaired by the **base excision repair (BER)** pathway. - The initial step in BER involves **DNA glycosylase**, which *removes* the damaged base (uracil) from the sugar-phosphate backbone by hydrolyzing the **N-glycosidic bond**, creating an **abasic site**. *Connecting the phosphodiester backbone* - This is the function of **DNA ligase**, which acts at the *final step* of DNA repair pathways to seal the nicks in the backbone. - It does not initiate the repair process for deaminated bases. *Cleavage of the phosphodiester bond 3' of damaged site* - This is typically performed by an **AP endonuclease (APE1)** after the abasic site has been created. - It is a *subsequent step* in BER, not the initial one for removing the damaged base itself. *Release of the damaged nucleotide* - While the damaged base is eventually *released*, the initial enzyme (DNA glycosylase) specifically removes the **base**, leaving the sugar and phosphate intact. - The entire nucleotide (base, sugar, and phosphate) is typically removed later by an **AP lyase** or APE1, after the initial glycosylase action. *Addition of free nucleotides to 3' end* - This is the function of **DNA polymerase**, which fills in the gap after the damaged nucleotide and surrounding region have been excised. - This occurs *after* the initial recognition and removal of the damaged base, not as the primary repair step.
Question 8: A 47-year-old man presents to his primary care physician for fatigue. Over the past 3 months, his tiredness has impacted his ability to work as a corporate lawyer. He denies any changes to his diet, exercise regimen, bowel movements, or urinary frequency. His past medical history is notable for obesity, type II diabetes mellitus, and hypertension. He takes metformin and enalapril. His family history is notable for colorectal cancer in his father and paternal grandfather and endometrial cancer in his paternal aunt. He has a 20-pack-year smoking history and drinks one 6-pack of beer a week. His temperature is 98.8°F (37.1°C), blood pressure is 129/71 mmHg, pulse is 82/min, and respirations are 17/min. On exam, he has conjunctival pallor. A stool sample is positive for occult blood. A colonoscopy reveals a small hemorrhagic mass at the junction of the ascending and transverse colon. Which of the following processes is likely impaired in this patient?
- A. Mismatch repair (Correct Answer)
- B. Homologous recombination
- C. Non-homologous end joining
- D. Nucleotide excision repair
- E. Base excision repair
Explanation: ***Mismatch repair*** - The patient's presentation with **colorectal cancer** at a relatively young age and a strong family history of various cancers (colorectal, endometrial) in **first-degree and second-degree relatives** suggests Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer). - **Lynch syndrome** is caused by inherited mutations in genes responsible for **DNA mismatch repair**, leading to an accumulation of errors and increased cancer risk. *Homologous recombination* - This repair mechanism is crucial for fixing **double-strand DNA breaks** using a homologous DNA template, important for genetic stability and primarily associated with genes like BRCA1/2. - While defects in homologous recombination can lead to cancer (e.g., **breast and ovarian cancers**), it is not the primary mechanism implicated in Lynch syndrome or the patient's specific presentation of colorectal and endometrial cancer families. *Non-homologous end joining* - This is another major pathway for repairing **double-strand DNA breaks**, but it does so by directly ligating the broken ends, often with some loss of genetic information, and does not rely on a homologous template. - Defects in non-homologous end joining are not typically linked to the specific spectrum of cancers seen in **Lynch syndrome**. *Nucleotide excision repair* - This pathway is responsible for removing bulky DNA lesions, such as those caused by **UV light (e.g., pyrimidine dimers)** or certain chemical mutagens, and its defects are associated with conditions like xeroderma pigmentosum. - The clinical picture and family history are not characteristic of disorders related to impaired **nucleotide excision repair**. *Base excision repair* - This repair pathway primarily corrects small, non-bulky DNA lesions, such as **oxidized, alkylated, or deaminated bases**, that do not distort the DNA helix. - While important for maintaining genomic integrity, defects in base excision repair are typically associated with different cancer susceptibilities and not the specific features of **Lynch syndrome**.
Question 9: An investigator is comparing DNA replication in prokaryotes and eukaryotes. He finds that the entire genome of E. coli (4 × 106 base pairs) is replicated in approximately 30 minutes. A mammalian genome (3 × 109 base pairs) is usually replicated within 3 hours. Which of the following characteristics of eukaryotic DNA replication is the most accurate explanation for this finding?
- A. Replication inhibition at checkpoint
- B. Absence of telomerase enzyme activity
- C. DNA compaction in chromatin
- D. Simultaneous replication at multiple origins (Correct Answer)
- E. More efficient DNA polymerase activity
Explanation: ***Simultaneous replication at multiple origins*** - Eukaryotic DNA replication initializes at **multiple origins of replication** along each chromosome, allowing synthesis to occur concurrently in many places. - This strategy compensates for the much larger eukaryotic genome size, enabling its complete replication within a reasonable timeframe despite slower polymerase speed compared to prokaryotes. *Replication inhibition at checkpoint* - **Cell cycle checkpoints**, such as those in G1, S, and G2 phases, ensure the integrity of DNA replication and repair. - While these checkpoints can *pause* or *inhibit* replication if errors occur, they do not fundamentally explain the *speed* or **efficiency** of replication across the entire genome. *Absence of telomerase enzyme activity* - **Telomerase** is an enzyme that maintains the ends of eukaryotic chromosomes (telomeres) by adding repetitive DNA sequences. - Its presence or absence is related to telomere length regulation and cellular aging, not the overall speed of genome replication. *DNA compaction in chromatin* - Eukaryotic DNA is compact and organized into **chromatin** within the nucleus, which presents a challenge to replication by limiting access to the DNA. - While enzymes must overcome this compaction, it is a *hindrance* rather than an enabler of replication speed. If anything, it would slow down replication. *More efficient DNA polymerase activity* - In actuality, **prokaryotic DNA polymerases** (e.g., DNA Pol III in *E. coli*) are generally more processive and faster than eukaryotic DNA polymerases. - Therefore, more efficient polymerase activity is not a characteristic that would explain the relatively fast replication of a larger eukaryotic genome.
Question 10: A 19-year-old man presents to his primary care physician for evaluation before going off to college. Specifically, he wants to know how to stay healthy while living outside his home. Since childhood he has suffered severe sunburns even when he goes outside for a small period of time. He has also developed many freckles and rough-surfaced growths starting at the same age. Finally, his eyes are very sensitive and become irritated, bloodshot, and painful after being outside. A defect in a protein with which of the following functions is most likely responsible for this patient's symptoms?
- A. Distinguishing methylated from unmethylated strands
- B. Recognition of chemically dimerized bases (Correct Answer)
- C. Endonucleolytic removal of bases from backbone
- D. Recognition of mismatched bases
- E. Sister chromatid binding and recombination
Explanation: ***Recognition of chemically dimerized bases*** - The patient's symptoms (severe sunburns, numerous freckles, rough growths, and ocular irritation) are highly suggestive of **Xeroderma Pigmentosum (XP)**, a genetic disorder characterized by extreme sensitivity to UV light. - XP is caused by a defect in **nucleotide excision repair (NER)**, specifically the proteins involved in **recognizing and excising DNA damage** like thymine dimers formed by UV radiation. *Distinguishing methylated from unmethylated strands* - This function is crucial for **DNA mismatch repair**, which corrects errors incorporated during DNA replication. - Defects in mismatch repair are associated with conditions like **Hereditary Nonpolyposis Colorectal Cancer (HNPCC)**, which presents differently from the patient's symptoms. *Endonucleolytic removal of bases from backbone* - This describes a step in **base excision repair (BER)**, which primarily handles small, non-helix-distorting base lesions. - While important for DNA repair, defects in BER would not typically lead to the severe UV sensitivity and skin manifestations seen in this patient. *Recognition of mismatched bases* - This is a key step in **DNA mismatch repair**, where enzymes identify incorrectly paired bases after DNA replication. - Deficiencies in this pathway lead to increased mutation rates and specific cancer syndromes, but not the severe UV sensitivity of Xeroderma Pigmentosum. *Sister chromatid binding and recombination* - This function is essential for proper chromosome segregation during cell division and for DNA repair via **homologous recombination**. - Defects here can lead to disorders with chromosomal instability but do not directly explain the extreme UV sensitivity and skin cancers characteristic of Xeroderma Pigmentosum.
Question 11: A mutant stem cell was created by using an inducible RNAi system, such that when doxycycline is added, the siRNA targeting DNA helicase is expressed, effectively knocking down the gene for DNA helicase. Which of the following will occur during DNA replication?
- A. The RNA primer is not created
- B. DNA is not unwound (Correct Answer)
- C. The two melted DNA strands reanneal
- D. DNA supercoiling is not relieved
- E. Newly synthesized DNA fragments are not ligated
Explanation: ***DNA is not unwound*** - **DNA helicase** is essential for unwinding the **double-stranded DNA** helix, separating it into two single strands. This process creates the **replication fork**. - Without functional DNA helicase due to **gene knockdown**, the DNA helix cannot be unwound, thus halting DNA replication. *The RNA primer is not created* - **RNA primers** are synthesized by **primase**, an enzyme distinct from DNA helicase. - While unwinding is necessary for primer synthesis, the *creation* of the primer itself is a function of primase. *The two melted DNA strands reanneal* - **Reannealing** of DNA strands is prevented by **single-strand binding proteins (SSBs)**, which bind to the separated single strands. - While helicase unwinds, SSBs specifically keep the strands apart to allow DNA polymerase access. *DNA supercoiling is not relieved* - **DNA supercoiling** is relieved by **topoisomerases**, enzymes that cut, unwind, and religate DNA strands to reduce torsional stress. - This is a distinct function from DNA helicase, which focuses on breaking hydrogen bonds between strands. *Newly synthesized DNA fragments are not ligated* - **Ligation** of newly synthesized **Okazaki fragments** on the lagging strand is performed by **DNA ligase**. - This process occurs downstream from the unwinding step facilitated by DNA helicase.
Question 12: A 3-year-old male child is found to have a disease involving DNA repair. Specifically, he is found to have a defect in the endonucleases involved in the nucleotide excision repair of pyrimidine dimers. Which of the following is a unique late-stage complication of this child's disease?
- A. Telangiectasia
- B. Colorectal cancer
- C. Malignant melanoma (Correct Answer)
- D. Lymphomas
- E. Endometrial cancer
Explanation: **Malignant melanoma** - The described condition is **xeroderma pigmentosum**, an autosomal recessive disorder characterized by a defect in **nucleotide excision repair (NER)**, specifically the inability to remove **pyrimidine dimers** caused by **UV radiation**. - This severely impaired DNA repair leads to an extreme predisposition to **UV-induced skin cancers**, including basal cell carcinomas, squamous cell carcinomas, and, most aggressively, **malignant melanoma**, which is a unique and life-threatening late-stage complication. *Telangiectasia* - **Telangiectasias** are dilated small blood vessels that appear on the skin or mucous membranes and can be associated with various conditions. - While skin abnormalities are prevalent in xeroderma pigmentosum due to sun damage, **melanoma** is a more specific and severe late-stage complication directly resulting from the DNA repair defect. *Colorectal cancer* - **Colorectal cancer** is typically associated with other DNA repair defects, such as those in the **mismatch repair system**, as seen in conditions like **Lynch syndrome**. - It is not a primary or most significant late-stage complication of xeroderma pigmentosum, which is primarily characterized by skin cancers. *Lymphomas* - **Lymphomas** are cancers of the lymphatic system, often linked to immune deficiencies or specific genetic translocations. - While individuals with genetic syndromes can have increased cancer risks, **lymphoma** is not the hallmark late-stage complication of xeroderma pigmentosum; skin cancers are the predominant concern. *Endometrial cancer* - **Endometrial cancer** is a gynecological cancer often associated with hormonal factors or genetic predispositions like Lynch syndrome, which involves mismatch repair defects. - This type of cancer is not a characteristic or unique late-stage complication of xeroderma pigmentosum, whose pathology is centered on **UV-induced DNA damage** and subsequent skin malignancies.
Question 13: An investigator is studying DNA repair processes in an experimental animal. The investigator inactivates a gene encoding a protein that physiologically excises nucleotides from damaged, bulky, helix-distorting DNA strands. A patient with a similar defect in this gene is most likely to present with which of the following findings?
- A. Ataxic gait and facial telangiectasias
- B. Malignant breast and ovarian growths
- C. Leukocoria and a painful bone mass
- D. Colorectal and endometrial cancers
- E. Dry skin and increased photosensitivity (Correct Answer)
Explanation: ***Dry skin and increased photosensitivity*** - The description of excising **nucleotides from damaged, bulky, helix-distorting DNA strands** points to a defect in **Nucleotide Excision Repair (NER)**. - Patients with defects in NER, such as those with **xeroderma pigmentosum**, are highly susceptible to UV-induced DNA damage, leading to **dry skin, increased photosensitivity**, and a high risk of skin cancers. *Ataxic gait and facial telangiectasias* - This constellation of symptoms is characteristic of **ataxia-telangiectasia**, a disorder caused by mutations in the **ATM gene**, which is involved in **DNA double-strand break repair**. - While a DNA repair defect, it's not primarily linked to the excision of bulky, helix-distorting DNA strands. *Malignant breast and ovarian growths* - These cancers are commonly associated with mutations in the **BRCA1 and BRCA2 genes**, which play crucial roles in **homologous recombination repair of DNA double-strand breaks**. - This type of repair is distinct from the excision of bulky, helix-distorting DNA strands described in the question. *Leukocoria and a painful bone mass* - **Leukocoria** can indicate **retinoblastoma**, linked to mutations in the **RB1 tumor suppressor gene**, which regulates the cell cycle but isn't primarily a DNA repair gene. - A painful bone mass could suggest **osteosarcoma**, which is sometimes seen in retinoblastoma patients but not directly related to the specific DNA repair defect described. *Colorectal and endometrial cancers* - These cancers are hallmarks of **Lynch syndrome (hereditary nonpolyposis colorectal cancer - HNPCC)**, which is caused by defects in **Mismatch Repair (MMR)** genes (e.g., MLH1, MSH2, MSH6, PMS2). - Mismatch repair corrects errors that arise during DNA replication, which is different from excising bulky, helix-distorting DNA damage.
Question 14: A 7-month-old boy presents to the family physician with extensive scaliness and pigmentation of sun-exposed skin areas. His mother says that these symptoms were absent until mid-spring and then became significantly worse after their trip to California in the summer. The child was born in December to a consanguineous couple after an uncomplicated pregnancy. He is breastfed and receives mashed potatoes, bananas, and carrots as complementary foods. His weight is 8.5 kg (18.7 lb) and length is 70 cm (2 ft 96 in). The patient’s vital signs are within normal limits for his age. On physical examination, there is freckling, scaling, and erythema on the sunlight-exposed areas of the face, trunk, and upper and lower extremities. No blistering, scarring, hypertrichosis, or alopecia is noted. The rest of the exam is unremarkable. Which process is most likely disrupted in this patient?
- A. Nucleotide-excision DNA repair (Correct Answer)
- B. Base-excision DNA repair
- C. Hydroxylation of proline and lysine in the procollagen molecule
- D. Conversion of uroporphyrinogen III to coproporphyrinogen III
- E. NAD production
Explanation: ***Nucleotide-excision DNA repair*** - The patient's symptoms (extensive scaliness, pigmentation, freckling, scaling, and erythema on sun-exposed areas) that worsen with sun exposure are characteristic of **xeroderma pigmentosum**. - This condition is caused by a defect in **nucleotide-excision repair (NER)**, which is essential for repairing DNA damage, particularly from UV radiation. *Base-excision DNA repair* - **Base-excision repair (BER)** primarily addresses single-base damage, like oxidized or alkylated bases, not the bulky adducts formed by UV light. - Defects in BER are associated with conditions like colorectal cancer, but not the specific photosensitivity seen here. *Hydroxylation of proline and lysine in the procollagen molecule* - This process is essential for proper collagen synthesis; defects lead to disorders like **Ehlers-Danlos syndrome** or **scurvy**. - These conditions manifest with skin fragility, bruising, and joint hypermobility, not the prominent photosensitivity observed. *Conversion of uroporphyrinogen III to coproporphyrinogen III* - This step is involved in **heme synthesis**; defects can lead to **porphyrias**, which often cause photosensitivity and blistering. - However, the patient's presentation of scaling, freckling, and erythema without blistering or scarring is less typical for porphyria. *NAD production* - **NAD (nicotinamide adenine dinucleotide)** is a crucial coenzyme in many metabolic pathways; its deficiency can lead to pellagra-like symptoms (dermatitis, diarrhea, dementia). - While pellagra can involve sun-exposed skin, it typically involves a more diffuse, symmetrically inflamed rash with hyperpigmentation and thickening, rather than the discrete freckling and scaling described.
Question 15: DNA replication is a highly complex process where replication occurs on both strands of DNA. On the leading strand of DNA, replication occurs uninterrupted, but on the lagging strand, replication is interrupted and occurs in fragments called Okazaki fragments. These fragments need to be joined, which of the following enzymes is involved in the penultimate step before ligation can occur?
- A. DNA gyrase
- B. DNA ligase
- C. DNA helicase
- D. DNA polymerase I (Correct Answer)
- E. DNA polymerase III
Explanation: **DNA polymerase I** - **DNA polymerase I** plays a crucial role in removing the **RNA primers** from the Okazaki fragments on the lagging strand. - After primer removal, it fills the resulting gaps with **deoxyribonucleotides** before DNA ligase seals the nicks. *DNA gyrase* - **DNA gyrase** (a type of **topoisomerase**) is involved in relieving **supercoiling** ahead of the replication fork. - It does not directly participate in the joining of Okazaki fragments, but rather in maintaining DNA topology during replication. *DNA ligase* - **DNA ligase** is responsible for the **final sealing** of the nicks between adjacent Okazaki fragments. - It forms a **phosphodiester bond** between the 3'-hydroxyl end of one fragment and the 5'-phosphate end of the next, following primer removal and gap filling. *DNA helicase* - **DNA helicase** unwinds the double-stranded DNA helix, separating the two strands at the **replication fork**. - This enzyme is essential for initiating replication but does not participate in processing Okazaki fragments. *DNA polymerase III* - **DNA polymerase III** is the primary enzyme responsible for the **elongation of new DNA strands** in both leading and lagging strand synthesis. - It synthesizes the actual Okazaki fragments but does not directly remove primers or fill the gaps.
Question 16: A 34-year-old woman comes to the physician for evaluation of a breast lump she noticed 2 days ago while showering. She has no history of major illness. Her mother died of ovarian cancer at age 38, and her sister was diagnosed with breast cancer at age 33. Examination shows a 1.5-cm, nontender, mobile mass in the upper outer quadrant of the left breast. Mammography shows pleomorphic calcifications. Biopsy of the mass shows invasive ductal carcinoma. The underlying cause of this patient's condition is most likely a mutation of a gene involved in which of the following cellular events?
- A. Repair of double-stranded DNA breaks (Correct Answer)
- B. Inhibition of programmed cell death
- C. Regulation of intercellular adhesion
- D. Activity of cytoplasmic tyrosine kinase
- E. Arrest of cell cycle in G1 phase
Explanation: ***Repair of double-stranded DNA breaks*** - The patient's **family history** (mother with ovarian cancer at 38, sister with breast cancer at 33) and early onset of **invasive ductal carcinoma** strongly suggest an inherited cancer syndrome. - **BRCA1 and BRCA2 genes** are tumor suppressor genes responsible for repairing **double-stranded DNA breaks**, and mutations in these genes significantly increase the risk of breast and ovarian cancers. *Inhibition of programmed cell death* - Mutations leading to the **inhibition of programmed cell death (apoptosis)**, such as those affecting the **Bcl-2 gene**, can contribute to cancer by allowing damaged cells to survive and proliferate. - While relevant to cancer pathogenesis, it is not the primary mechanism associated with the specific familial breast/ovarian cancer pattern seen here, which points more directly to DNA repair defects. *Regulation of intercellular adhesion* - Defects in **intercellular adhesion**, often involving **E-cadherin** (CDH1 gene) mutations, are associated with cancers like **lobular breast carcinoma** and **hereditary diffuse gastric cancer**. - This patient has **invasive ductal carcinoma**, and the specific familial pattern is less characteristic of intercellular adhesion defects. *Activity of cytoplasmic tyrosine kinase* - Abnormal **cytoplasmic tyrosine kinase activity** is implicated in various cancers (e.g., **HER2/neu** amplification in breast cancer, **BCR-ABL** fusion in CML). - While HER2/neu overexpression is common in breast cancer, it is typically a somatic mutation or amplification, and not the underlying germline defect explaining the strong family history of early-onset breast and ovarian cancer. *Arrest of cell cycle in G1 phase* - The **arrest of the cell cycle at the G1 phase** is mainly regulated by **p53** and **Rb tumor suppressor genes**, which prevent uncontrolled cell division. - While mutations in these genes are crucial in many cancers, the specific familial pattern (breast and ovarian cancer) points more strongly to defects in homologous recombination via BRCA1/2, a different DNA repair pathway.
Question 17: A 17-year-old patient presents to the emergency department with left wrist pain after falling off of his bike and landing on his left hand. On physical exam the thenar eminence is red, swollen, and tender to palpation, so a radiograph is ordered. The patient is worried because he learned in biology class that radiography can cause cancer through damaging DNA but the physician reassures him that radiographs give a very minor dose of radiation. What is the most common mechanism by which ionizing radiation damages DNA?
- A. Strand breakage (Correct Answer)
- B. Thymidine dimer formation
- C. Microsatellite instability
- D. Cyclobutane pyrimidine dimer formation
- E. Cytosine deamination
Explanation: ***Strand breakage*** - Ionizing radiation, such as X-rays, directly or indirectly causes **breaks in the phosphodiester backbone** of DNA, resulting in single or double-strand breaks. - **Double-strand breaks** are particularly dangerous as they are difficult to repair and can lead to chromosomal rearrangements and cell death or malignant transformation. *Thymidine dimer formation* - This is primarily caused by **ultraviolet (UV) radiation**, not ionizing radiation like X-rays. - **UV radiation** causes covalent bonds between adjacent pyrimidine bases, particularly thymine, leading to the formation of thymine dimers. *Microsatellite instability* - This is a hallmark of defects in **DNA mismatch repair pathways**, often associated with hereditary disorders like Lynch syndrome or certain sporadic cancers. - It involves changes in the length of **microsatellites** (short, repetitive DNA sequences) due to insertion or deletion errors, not direct radiation damage. *Cyclobutane pyrimidine dimer formation* - Similar to thymidine dimers, **cyclobutane pyrimidine dimers (CPDs)** are the most common photoproducts formed in DNA after exposure to **UV radiation**. - These dimers distort the DNA helix and interfere with replication and transcription, but are not characteristic of ionizing radiation damage. *Cytosine deamination* - This is a spontaneous chemical reaction where a **cytosine base (C)** loses its amino group and is converted to **uracil (U)**. - It is a common endogenous DNA lesion that can lead to C-to-T transition mutations if not repaired, but it is not directly induced by ionizing radiation.
Question 18: A 5-month-old male infant from a consanguineous marriage presents with severe sunburns and freckling in sun exposed areas. The mother explains that the infant experiences these sunburns every time the infant goes outside despite applying copious amounts of sunscreen. Which of the following DNA repair mechanisms is defective in this child?
- A. Non-homologous end joining
- B. Homologous recombination
- C. Base excision repair
- D. Mismatch repair
- E. Nucleotide excision repair (Correct Answer)
Explanation: ***Nucleotide excision repair*** - The symptoms of **severe sunburns** and **freckling in sun-exposed areas** are classic manifestations of **Xeroderma Pigmentosum (XP)**. - XP is caused by a defect in **nucleotide excision repair (NER)**, which is crucial for removing **UV-induced DNA damage**, such as **pyrimidine dimers**. *Non-homologous end joining* - This mechanism repairs **double-strand DNA breaks** by directly ligating the broken ends, often with some loss of genetic information. - Defects in non-homologous end joining are associated with conditions like **immunodeficiency** and increased cancer risk, but not with UV sensitivity like XP. *Homologous recombination* - This high-fidelity repair pathway uses a **homologous DNA template** to accurately repair **double-strand breaks** and interstrand crosslinks. - Impaired homologous recombination is linked to conditions like **Fanconi anemia** and increased risk of certain cancers, but not primarily to UV hypersensitivity. *Base excision repair* - **Base excision repair (BER)** is responsible for removing **damaged or modified bases** from DNA, such as oxidized or alkylated bases. - Defects in BER can lead to increased spontaneous mutagenesis and cancer, but do not explain the specific sensitivity to UV light seen in this infant. *Mismatch repair* - **Mismatch repair (MMR)** corrects errors that occur during DNA replication, such as **base mismatches** or small insertions/deletions. - Defective MMR is strongly associated with **hereditary nonpolyposis colorectal cancer (Lynch syndrome)**, but not with severe reactions to sun exposure.
Question 19: A 5-year-old girl is brought to the physician by her mother because of a 1-month history of a painful ulcer on her face. She has developed painful sunburns in the past with minimal UV exposure. Examination of the skin shows a 2-cm ulcerated nodule on the left cheek. There are scaly, hyperpigmented papules and plaques over the skin of the entire body. Ophthalmologic examination shows decreased visual acuity, clouded corneas, and limbal injection. Examination of a biopsy specimen from the facial lesion shows poorly-differentiated squamous cell carcinoma. Impairment of which of the following proteins is the most likely cause of this patient's condition?
- A. Rb nuclear protein
- B. Base-specific glycosylase
- C. Excision endonuclease (Correct Answer)
- D. ATM serine/threonine kinase
- E. DNA helicase
Explanation: ***Excision endonuclease*** - This patient's presentation with **painful sunburns**, **early-onset squamous cell carcinoma** on the face, and **ocular abnormalities (clouded corneas, decreased visual acuity)** is highly suggestive of **xeroderma pigmentosum (XP)**. - XP is an autosomal recessive disorder caused by a defect in **nucleotide excision repair (NER)**, which is responsible for removing DNA damage primarily induced by **UV radiation**. **Excision endonucleases** are key enzymes in the initiation phase of NER, recognizing and excising the damaged DNA segment. *Rb nuclear protein* - The **Rb nuclear protein** is a tumor suppressor involved in cell cycle regulation (G1/S checkpoint). - Impairment of Rb is associated with **retinoblastoma** and several other cancers, but not typically with this specific constellation of light sensitivity, skin cancer, and ocular damage seen in XP. *Base-specific glycosylase* - **Base-specific glycosylases** are involved in **base excision repair (BER)**, which primarily corrects small, non-helix-distorting base lesions (e.g., deaminated or alkylated bases). - While important for DNA repair, defects in BER would not explain the extreme UV sensitivity and subsequent skin cancers characteristic of xeroderma pigmentosum, as these are primarily linked to UV-induced pyrimidine dimers. *ATM serine/threonine kinase* - **ATM (ataxia-telangiectasia mutated) kinase** is a critical protein involved in initiating the cellular response to **DNA double-strand breaks**. - Defects in ATM cause **ataxia-telangiectasia**, characterized by cerebellar ataxia, immunodeficiency, and a predisposition to lymphoid malignancies, but not the specific skin and eye findings of XP. *DNA helicase* - **DNA helicases** are enzymes that unwind DNA and are involved in various DNA processes, including replication, recombination, and repair. - While critical for many functions, a general defect in **DNA helicase** would lead to a broader range of severe developmental and cellular defects, and is not specifically linked to the clinical phenotype of xeroderma pigmentosum which results from specific NER pathway defects.
Question 20: A pathologist is investigating the cytology of cells that have been infected with a particularly virulent strain of the influenza virus. The physician suspects that the virus results in cell death after viral replication in order to expedite the spread of the virus. She recalls that there are three known biochemical mechanisms of initiating programmed cellular death: 1) transmembrane receptor-mediated interaction, 2) stimuli producing intracellular signals leading to mitochondrial-initiated events, and 3) release of cytoplasmic granules into a cell via a perforin molecule. Which of the following biochemical components plays a common role in all of these 3 processes?
- A. Bcl-2
- B. FAS ligand
- C. Caspase-3 (Correct Answer)
- D. Bax
- E. CD-95 protein
Explanation: ***Caspase-3*** - **Caspase-3** is a crucial "executioner" caspase that is activated in all three described pathways of programmed cell death (apoptosis): **extrinsic (receptor-mediated)**, **intrinsic (mitochondrial)**, and **granzyme B-induced pathways**. - Once activated, **caspase-3** cleaves various cellular substrates, leading to the characteristic biochemical and morphological changes associated with **apoptosis**, such as DNA fragmentation and chromatin condensation. *Bcl-2* - **Bcl-2** is an **anti-apoptotic protein** that primarily acts by inhibiting the release of pro-apoptotic factors from the mitochondria, thereby preventing the mitochondrial (intrinsic) pathway of apoptosis. - It does not play a direct role in the extrinsic or granzyme B-mediated pathways and its function is generally to **inhibit** apoptosis, not mediate its common steps. *FAS ligand* - **FAS ligand (FasL)** is a **death ligand** that binds to the **FAS receptor (CD95)** on target cells, initiating the **extrinsic (receptor-mediated)** pathway of apoptosis. - While essential for this specific pathway, **FasL** is not involved in the mitochondrial or granzyme B-mediated pathways of cell death. *Bax* - **Bax** is a **pro-apoptotic protein** that belongs to the Bcl-2 family and is critical for the **mitochondrial (intrinsic)** pathway of apoptosis. - Upon activation, **Bax** permeabilizes the outer mitochondrial membrane, leading to the release of cytochrome c, but it is not directly involved in the extrinsic or granzyme B-mediated pathways. *CD-95 protein* - **CD-95 protein**, also known as **FAS receptor**, is a **death receptor** that, upon binding to its ligand (FASL), initiates the **extrinsic (receptor-mediated)** pathway of apoptosis. - Like FAS ligand, its role is specific to the extrinsic pathway and it is not a common component across all three described mechanisms of programmed cell death.
Practice by Chapter
Types of DNA damage
Practice Questions
Base excision repair
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Nucleotide excision repair
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Mismatch repair
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Double-strand break repair
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Homologous recombination
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Non-homologous end joining
Practice Questions
Direct repair mechanisms
Practice Questions
DNA damage response signaling
Practice Questions
DNA repair deficiency syndromes
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Cancer susceptibility and DNA repair
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Aging and DNA repair
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