On November 13, 2017, Dr. Jun Huang’s research group published a research article entitled “BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability” in Nature Communications. 

BRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here, we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and relies on the well-defined DNA damage signaling pathway involving 53BP1 and its downstream effector RIF1. We further show that the 53BP1-RIF1 axis promotes toxic end-joining events via the retention of Artemis at DNA damage sites. We propose that BRCA2 antagonizes 53BP1/RIF1/Artemis-dependent c-NHEJ and alt-NHEJ to prevent gross genomic instability in a RAD51-independent manner.

Figure: A model showing the role of BRCA2 in maintaining genome stability

Link: https://www.nature.com/articles/s41467-017-01759-y