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BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability

Jinhua Han,Chunyan Ruan,Michael S. Y. Huen,Jiadong Wang,Anyong Xie,Chun Fu,Ting Liu,Jun Huang

Published 2017 in Nature Communications

ABSTRACT

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 rely on the well-defined DNA damage signaling pathway involving the pro-c-NHEJ factor 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. Accordingly, loss of 53BP1, RIF1, or Artemis prolongs the stability of RPA-coated DSB intermediates in BRCA2-deficient cells and restores nuclear integrity. We propose that BRCA2 antagonizes 53BP1, RIF1, and Artemis-dependent c-NHEJ and alt-NHEJ to prevent gross genomic instability in a RAD51-independent manner.The genomic instability phenotype characteristic of BRCA2-deficient cells is not fully mechanistically understood. Here the authors show BRCA2 inactivation destabilizes RPA-coated single-stranded DNA and leads to toxic non homologous end-joining events.

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