DNA repair: BRCA and PARP inhibitors: practice question

A Biochemistry question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Biochemistry · DNA repair: BRCA and PARP inhibitors

Sample item

A 52-year-old woman with high-grade serous ovarian cancer carrying a germline BRCA1 mutation is treated with olaparib. Which principle explains why the drug is selectively toxic to her tumour cells?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

C. Blocked repair of single-strand breaks leaves double-strand breaks that BRCA-deficient cells cannot repair by homologous recombination

BRCA1 and BRCA2 are needed for homologous recombination repair of double-strand breaks. PARP inhibitors block PARP-mediated repair of single-strand breaks, which then collapse at replication forks into double-strand breaks. Normal cells repair them by homologous recombination, whereas BRCA-deficient tumour cells cannot, an example of synthetic lethality.

Option by option

  • A. Olaparib inhibits mismatch repair, which is already deficient in BRCA-mutated cells

    Mismatch repair is carried out by MSH and MLH proteins, not BRCA, and olaparib does not target it.

  • B. Olaparib incorporates into DNA and causes chain termination

    Olaparib acts through enzyme inhibition and is not a chain-terminating nucleoside analogue.

  • C. Blocked repair of single-strand breaks leaves double-strand breaks that BRCA-deficient cells cannot repair by homologous recombination (correct)

    Two defective repair pathways together are lethal to tumour cells.

  • D. Olaparib activates p53 in cells that lack the BRCA gene

    Olaparib does not activate p53 as its primary mechanism.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Biochemistry question

What is the answer to this Biochemistry question?

The best answer is C, Blocked repair of single-strand breaks leaves double-strand breaks that BRCA-deficient cells cannot repair by homologous recombination. BRCA1 and BRCA2 are needed for homologous recombination repair of double-strand breaks.

Why is "Olaparib inhibits mismatch repair, which is already deficient in BRCA…" not the answer?

Mismatch repair is carried out by MSH and MLH proteins, not BRCA, and olaparib does not target it.

Why is "Olaparib incorporates into DNA and causes chain termination" not the answer?

Olaparib acts through enzyme inhibition and is not a chain-terminating nucleoside analogue.

Why is "Olaparib activates p53 in cells that lack the BRCA gene" not the answer?

Olaparib does not activate p53 as its primary mechanism.

What concept does this question test?

It tests DNA repair: BRCA and PARP inhibitors in Biochemistry. PARP inhibitors block PARP-mediated repair of single-strand breaks, which then collapse at replication forks into double-strand breaks. Normal cells repair them by homologous recombination, whereas BRCA-deficient tumour cells cannot, an example of synthetic lethality.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study DNA repair: BRCA and PARP inhibitors?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.