A 38-year-old man presents with concerns after finding out that his father was recently diagnosed with colon cancer. Family history is only significant for his paternal grandfather who also had colon cancer. A screening colonoscopy is performed, and a polyp is found in the ascending (proximal) colon, which on biopsy shows adenocarcinoma. A mutation in a gene that is responsible for which of the following cellular functions is the most likely etiology of this patient’s cancer?

Inhibits progression from G1 to S phase

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?

Nonhomologous end joining repair

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?

Nonhomologous end joining repair

A 19-year-old woman presents to the physician for a routine health maintenance examination. She has a past medical history of gastroesophageal reflux disease. She recently moved to a new city to begin her undergraduate studies. Her father was diagnosed with colon cancer at age 46. Her father's brother died because of small bowel cancer. Her paternal grandfather died because of stomach cancer. She takes a vitamin supplement. Current medications include esomeprazole and a multivitamin. She smoked 1 pack of cigarettes daily for 3 years but quit 2 years ago. She drinks 1–2 alcoholic beverages on the weekends. She appears healthy. Vital signs are within normal limits. Physical examination shows no abnormalities. Colonoscopy is unremarkable. Germline testing via DNA sequencing in this patient shows mutations in DNA repair genes MLH1 and MSH2. Which of the following will this patient most likely require at some point in her life?

Annual colonoscopy beginning at 20–25 years of age

Surgical removal of a desmoid tumor

Prophylactic proctocolectomy with ileoanal anastomosis

Measurement of carcinoembryonic antigen and CA 19-9 yearly

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?

Connecting the phosphodiester backbone

Cleavage of the phosphodiester bond 3' of damaged site

Release of the damaged nucleotide

Addition of free nucleotides to 3' end

Cancer susceptibility and DNA repair for USMLE Step 2 CK: High-Yield Biochemistry Lessons

DNA Repair & Cancer - Guardian Genes Fail

Inherited mutations in DNA repair genes dramatically increase cancer susceptibility by allowing mutations to accumulate.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC/Lynch Syndrome)
- Mechanism: Defective Mismatch Repair (MMR).
- Genes: MSH2, MLH1, MSH6, PMS2.
Xeroderma Pigmentosum (XP)
- Mechanism: Defective Nucleotide Excision Repair (NER) of UV-induced pyrimidine dimers.
BRCA1/BRCA2 Syndromes
- Mechanism: Impaired Homologous Recombination for double-strand break repair.

⭐ Ataxia-telangiectasia, caused by a defect in the ATM gene, disrupts Non-Homologous End Joining (NHEJ), leading to sensitivity to ionizing radiation.

DNA Repair Deficiencies and Associated Tumors

Mismatch Repair (MMR) - Lynch's Wrong Turn

Function: Corrects errors (mismatches, insertions, deletions) made during DNA replication. A "spell-checker" for newly synthesized DNA.
Mechanism:
- Proteins (e.g., MSH, MLH) recognize the mismatch on the new daughter strand.
- The erroneous segment is excised and replaced.
Key Genes: MSH2, MLH1, MSH6, PMS2. Mutations impair the repair process.
Pathology: Germline mutations cause Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer - HNPCC).
Hallmark: Leads to microsatellite instability (MSI).

⭐ Lynch syndrome significantly increases the lifetime risk of colorectal, endometrial, ovarian, and stomach cancers.

Mismatch repair pathway and cancer susceptibility

Nucleotide Excision Repair (NER) - Sun's Kiss of Death

Function: Corrects bulky, helix-distorting lesions. Occurs in G1 phase of the cell cycle.
Mechanism:
- Specific endonucleases recognize and excise damaged DNA strands.
- DNA Polymerase fills the single-stranded gap.
- DNA Ligase seals the final nick.
Classic Lesion: Pyrimidine dimers caused by UV light exposure.
Associated Disease: Xeroderma Pigmentosum (XP)
- Autosomal recessive; defective NER prevents repair of pyrimidine dimers.
- Presents with extreme sun sensitivity, ↑ risk of skin cancers.

Nucleotide Excision Repair (NER) pathway steps

⭐ NER is also crucial for repairing bulky adducts from environmental carcinogens, like benzo[a]pyrene in tobacco smoke.

Double-Strand Breaks - Broken Ladders, Bad News

The most severe form of DNA damage, risking genomic integrity.
Two primary repair mechanisms exist with distinct fidelity and cell cycle timing.
Homologous Recombination (HR):
- High-fidelity, error-free pathway using a sister chromatid as a template.
- Active only in S/G2 phases.
- Key genes: ATM, BRCA1, BRCA2.
⭐ Mutations in BRCA1 and BRCA2 cripple HR, dramatically increasing lifetime risk for breast, ovarian, prostate, and pancreatic cancers.
Non-Homologous End Joining (NHEJ):
- Error-prone, dominant pathway active throughout the cell cycle.
- Directly ligates broken ends, often causing small insertions or deletions (indels).

High‑Yield Points - ⚡ Biggest Takeaways

Inherited mutations in DNA repair genes are a hallmark of many cancer predisposition syndromes.

Mismatch Repair defects lead to Lynch Syndrome (HNPCC), primarily causing colorectal and endometrial cancer.

Nucleotide Excision Repair failure causes Xeroderma Pigmentosum, leading to extreme UV sensitivity and skin cancers.

Homologous Recombination defects (e.g., BRCA1/2) dramatically increase risk for breast, ovarian, and prostate cancers.

ATM gene mutations cause Ataxia-Telangiectasia, impairing double-strand break repair.

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