53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in

Zachary Mirman, Francisca Lottersberger, Hiroyuki Takai, Tatsuya Kibe, Yi Gong, Kaori Takai, Alessandro Bianchi, Michal Zimmermann, Daniel Durocher and Titia Lange ()
Additional contact information
Zachary Mirman: Rockefeller University
Francisca Lottersberger: Rockefeller University
Hiroyuki Takai: Rockefeller University
Tatsuya Kibe: Rockefeller University
Yi Gong: Rockefeller University
Kaori Takai: Rockefeller University
Alessandro Bianchi: Rockefeller University
Michal Zimmermann: Rockefeller University
Daniel Durocher: Mount Sinai Hospital
Titia Lange: Rockefeller University

Nature, 2018, vol. 560, issue 7716, 112-116

Abstract: Abstract In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair—which requires a 3′ overhang—and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3–8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7–SHLD1–SHLD2–SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6–9. Here we address the mechanism by which 53BP1–RIF1–shieldin regulates the generation of recombinogenic 3′ overhangs. We report that CTC1–STN1–TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)–primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST–Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin.

Date: 2018
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DOI: 10.1038/s41586-018-0324-7

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