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BRCA2 DNA repair errors implicated in infertility

23 August 2021
Appeared in BioNews 1109

BRCA2 mutations may be implicated in infertility, as well as increasing cancer risk, according to new research.

BRCA2 protein complexes work to repair DNA breaks within cells, protecting the integrity of the genome. Mutations in the BRCA2 gene can cause faulty DNA repair mechanisms which in turn confer increased cancer risk (particularly for breast and ovarian cancers). BRCA2 proteins also play a role in the repair of DNA breaks during meiosis, the cell division process by which gametes (eggs and sperm) are made.

'While we have known BRCA2 was necessary for DNA recombination in meiosis, we didn't know how it was able to do this critical job efficiently,' said study author Dr Jayakrishnan Nandakumar, from the University of Michigan.

The process of DNA breaking and repair in meiosis occurs as part of a natural event called crossover, where paired chromosomes are purposely broken, mixed up, and joined back together to 'switch' genes with each other, in order to generate genetic diversity in the gametes. 

In collaboration with the University of Gothenburg in Sweden, the project revealed the structure of a meiosis-specific protein complex involving BRCA2. BRCA2 proteins form a 'sandwich' structure along with proteins called MEILB2, to repair these breaks. 

The researchers found that the 'sandwich' shape of the BRCA2-MEIL2B complex is important to precisely join DNA breakpoints together. DNA repair failures or imprecisions during crossover can lead to genetic defects in the gametes, which may cause infertility.

MEILB2, which is normally only found in cells undergoing meiosis, has also been detected in cancers. The researchers suggest that the aberrant presence of MEILB2 in cancer cells may be preventing normal BRCA2-mediated repair from occurring. 

'The MEILB2 that is part of this repair complex is only supposed to be present in cells that undergo meiosis but MEILB2 has also been found in several cancers. It may be that MEILB2 is very efficiently "hijacking" the BRCA2 in cancer cells, preventing proper repair of the DNA', said Dr Nandakumar.

The study was published in Nature Structural & Molecular Biology.

SOURCES & REFERENCES
Structure of a meiosis-specific complex central to BRCA2 localisation at recombination sites
Nature Structural and Molecular Biology |  9 August 2021
University of Michigan researchers solve structure of BRCA2 protein complex important in DNA repair
University of Michigan News |  13 August 2021
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