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

journal contribution
posted on 2023-06-09, 14:31 authored by Zachary Mirman, Francisca Lottersberger, Hiroyuki Takai, Tatsuya Kibe, Yi Gong, Kaori Takai, Alessandro BianchiAlessandro Bianchi, Michal Zimmerman, Daniel Durocher, Tittia de Lange
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)3,4,5,6,7,8. 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 inhibitors4,6,7,8,9. 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-a (Pola)–primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Pola 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, Pola inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST–Pola-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Nature

ISSN

0028-0836

Publisher

Nature Publishing Group

Volume

560

Page range

112-116

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-08-14

First Open Access (FOA) Date

2019-01-18

First Compliant Deposit (FCD) Date

2018-08-14

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