Question

1) Describe how wild-type BRCA2 is thought to be involved in controlling the repair of DNA double-stranded breaks (DSB) by homologous recombination in mammalian cells? 2) Can you propose a possible therapeutic strategy(ies) that might correct any homologous recombination deficiencies in cells expressing BRCA26174delt protein?| 3) Explain the concept of “synthetic lethality”. How might you use this strategy to eliminate cells expressing BRCA26174delt protein.

Hi! If you're able to answer any of these, it would be much appreciated! Also, if you used any articles for your answers, please add the title so I can find them too!! Thank you!

Answer 1

The answer to the first part of question is as follows,

Various environmental insults are responsible double-strand breaks in DNA but ionizing radiation is by far the most likely cause.

Following are 3 mechanisms for DSB,

1. non-homologous end joining (NHEJ) repair

2. homologous recombination repair (HRR)

3. single-strand annealing (SSA)

NHEJ and SSA are more prone to errors while HRR is practically error-free, reason being, NHEJ and SSA do not involve sister chromatids during repair but HRR uses homologous chromosomes. Both NHEJ and HRR are active in mammalian cells and involved in DSB repair. Any loss of these repair processes can cause chromosomal rearrangements.

DSB repair can happen in the following steps,

1. Ends are resected exonucleolytically in 5' to 3' direction.

2. It produces long 3' single-stranded tails. These tails invade the homologous chromosome during meiosis or sister chromatid during mitosis at the site of homologous sequence.

3. The process of resection involves Rad50/Mre11/Xrs2 protein complex

4. Strand invasion and process of exchange is a key step which occurs in Rad51 filament.

5. 3' end of invading strands are used as primers for repair (semi-conservative).

6. At the end of the process, one new strand is present in each donor and recipient.

7. The joint molecule contains a heteroduplex region with a border of 2 branched structures called Holliday junction (after the name of the discoverer, Holliday).

8. Endonucleolytic resolution of Holliday junction yields 2 products: a crossover product called splice recombinant a non-crossover product called patch recombinant.

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