DNA Replication & Repair

Correct: C

Xeroderma Pigmentosum. UV radiation (UVB specifically) causes adjacent pyrimidines (usually thymine-thymine) to form covalent cyclobutane rings called pyrimidine dimers. These are bulky, helix-distorting lesions that can only be repaired by Nucleotide Excision Repair (NER). XP patients have NER gene mutations (XPA-XPG), so UV dimers accumulate with every sun exposure and cause mutations driving skin cancers.

A (Base deamination): Good instinct on base-level DNA damage, because deamination does alter bases. But what scale of damage is it? A single small base change, the substrate for base excision repair, where a glycosylase flips out one base. Is a UV dimer a single-base tweak or a bulky helix kink requiring a 25-nucleotide patch? The latter, which is NER. Match the lesion to the crew. Single-base deamination is repaired by base excision repair; a bulky UV pyrimidine dimer is repaired by NER.

B (IDLs at microsatellites): Tempting because microsatellite instability sounds like accumulated error. But where do insertion-deletion loops come from? Polymerase slippage at repeats, corrected by mismatch repair, whose failure is Lynch syndrome in colon and endometrium. Does that match a sun-sensitive child with skin cancer? No. UV photoproducts are an NER problem. Insertion-deletion loops at microsatellites are a mismatch repair (Lynch) problem; UV pyrimidine dimers are an NER (xeroderma pigmentosum) problem.

D (Double-strand breaks): Good instinct on serious physical damage, but which crews fix a double-strand break? Homologous recombination and non-homologous end joining. Does UV light sever both strands across from each other, or weld two pyrimidines on one strand? It welds one strand into a bulky lesion, the NER substrate. Different damage, different crew. Double-strand breaks are repaired by HR or NHEJ; bulky single-strand UV dimers are repaired by NER.

Correct: A

Lynch Syndrome (HNPCC) caused by MLH1 mutation. After colorectal cancer, endometrial cancer is the second most common malignancy in Lynch Syndrome, with lifetime risk of 40-60% in women. Mismatch repair deficiency allows replication errors to accumulate in rapidly dividing endometrial cells. Annual endometrial sampling and transvaginal ultrasound (or prophylactic hysterectomy) are guideline-recommended.

B (Mammography from age 30): Tempting because breast cancer is the first hereditary cancer most people associate with genetic testing. But which syndrome puts mammography from age 30 on the calendar? BRCA1/2, an HR defect. Does this MLH1 patient have an HR defect, or a mismatch repair defect? Mismatch repair, which targets colon, endometrium, and ovary, not breast. Screen the organ the mutation actually threatens. BRCA1/2 surveillance starts breast imaging early; Lynch (mismatch repair) surveillance prioritizes the endometrium, so this is the wrong syndrome's protocol.

C (Skin melanoma surveillance): Good instinct, since a few inherited syndromes do raise melanoma risk. But which ones? BRCA2 and CDKN2A carriers, not MLH1. Where does a mismatch repair defect strike? High-turnover epithelium: gut and endometrium, not stable melanocytes. The mutation here does not meaningfully raise melanoma risk. Melanoma surveillance fits BRCA2 or CDKN2A; an MLH1 Lynch patient is screened for endometrial, not melanoma, risk.

D (Lung CT for lung cancer): Who gets low-dose lung CT? Heavy smokers with high absolute lung cancer risk, not Lynch patients. Does mismatch repair failure target the lung? No, it targets colon and uterus. Match surveillance to the organ the mutation threatens, and the lung is not on the Lynch list. Lung CT screens smokers; Lynch surveillance is colonoscopy plus endometrial sampling, because mismatch repair failure hits the gut and uterus.

Correct: D

BRCA2 is a central component of Homologous Recombination (HR). After a double-strand break in S or G2 phase, the broken ends are resected to expose single-stranded DNA. BRCA2's specific function is to load RAD51 recombinase onto these single-stranded 3' tails. RAD51 then catalyzes strand invasion into the sister chromatid for error-free repair. Without BRCA2, RAD51 cannot be properly loaded and HR is severely impaired, forcing the cell to use error-prone NHEJ instead.

A (Nucleotide excision repair): Good instinct that BRCA2 is a DNA repair protein, so any repair pathway feels plausible. But what lesion does NER handle? Bulky helix-distorting lesions like UV dimers, not broken strands. Is BRCA2 called for a warped base or for a snapped chromosome? A snapped chromosome, the double-strand break. Different damage, different crew. NER removes bulky lesions like UV dimers (the XP pathway); BRCA2 loads RAD51 for high-fidelity HR repair of double-strand breaks.

B (Mismatch repair): Tempting because mismatch repair is another cancer-predisposition pathway. But what does it correct? Base mismatches and slippage loops after replication, and BRCA2 plays no part in it. When is BRCA2 summoned? Only when both strands break. Match BRCA2 to the double-strand break, not the post-replication typo. Mismatch repair fixes replication mismatches (Lynch, microsatellite instability); BRCA2 enables HR repair of double-strand breaks and predisposes to breast and ovarian cancer.

C (Non-homologous end joining): Good instinct, since NHEJ is one of the two double-strand break pathways, so you are in the right damage category. But does NHEJ need BRCA2? No, it ligates ends without a template. BRCA2 is specific to the other branch, homologous recombination, which copies the intact sister chromatid for a faithful repair. Right damage, wrong branch. NHEJ is template-free and BRCA2-independent; HR is the high-fidelity branch that needs BRCA2 to load RAD51 onto resected ends.

Clinical corollary: BRCA2 = FANCD1 (Fanconi Anemia complementation group D1). Homozygous BRCA2 mutations cause Fanconi Anemia phenotype (aplastic anemia, AML) in childhood. Heterozygous mutations cause breast/ovarian cancer predisposition in adulthood.

Correct: C

Telomerase is a reverse transcriptase that uses its own RNA template (TERC) to add TTAGGG repeats to chromosome ends. In normal somatic cells, the TERT gene (catalytic subunit) is epigenetically silenced after development. Without telomerase, chromosomes shorten with each replication cycle, triggering senescence or apoptosis. This is a built-in tumor suppressor mechanism.

Cancer cells overcome this by reactivating TERT, most commonly through TERT promoter mutations (creating new transcription factor binding sites), TERT amplification, or ALT (Alternative Lengthening of Telomeres).

A (Frameshift in TERT gene): Good instinct, since TERT reactivation is the mechanism, so a mutation in TERT feels right. But where does that reactivation happen, the coding sequence or the promoter? Mostly the promoter, where new transcription-factor binding sites switch the gene back on. A coding frameshift would break the enzyme, not re-express a working one. The cell needs a functional enzyme turned back on, which is a regulatory change. Cancer reactivates TERT mainly through promoter mutations or amplification, re-expressing a functional enzyme, not through coding frameshifts.

B (Normal cells lack TERC): Tempting because the RNA template TERC sounds like the missing piece. But is TERC actually scarce in somatic cells? No, it is broadly expressed. Which component is the silenced, rate-limiting one? TERT, the catalytic subunit. The blueprint is on the shelf; the licensed builder is what somatic cells withhold. TERC is widely expressed; somatic cells silence the catalytic subunit TERT, and cancers reactivate TERT, not re-acquire TERC.

D (Antiviral reverse transcriptase silencing): Interesting framing, but ask what silencing TERT actually accomplishes. It stops telomere maintenance so cells eventually senesce, a tumor-suppressor brake. Does that have anything to do with blocking retroviruses? No, those are separate regulatory circuits. The purpose of TERT silencing is preventing immortality, not viral defense. TERT silencing is a tumor-suppressor brake against replicative immortality; antiviral defense is an unrelated system.