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Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint

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Version 2 2023-06-12, 09:08
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journal contribution
posted on 2023-06-12, 09:08 authored by Nicolas Bigot, Matthew Day, Robbie A Baldock, Felicity Watts, Antony OliverAntony Oliver, Laurence PearlLaurence Pearl
Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ubiquitylation on other proteins, and are themselves carriers of such regulatory signals. Here we show that the DNA damage checkpoint regulating S-phase entry is controlled by a phosphorylation-dependent interaction of 53BP1 and TOPBP1. BRCT domains of TOPBP1 selectively bind conserved phosphorylation sites in the N-terminus of 53BP1. Mutation of these sites does not affect formation of 53BP1 or ATM foci following DNA damage, but abolishes recruitment of TOPBP1, ATR and CHK1 to 53BP1 damage foci, abrogating cell cycle arrest and permitting progression into S-phase. TOPBP1 interaction with 53BP1 is structurally complimentary to its interaction with RAD9-RAD1-HUS1, allowing these damage recognition factors to bind simultaneously to the same TOPBP1 molecule and cooperate in ATR activation in the G1 DNA damage checkpoint.

Funding

Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discovery; Cancer Research UK; C302/A14532

Structural Biology of DNA Damage Response and Repair Mechanisms; CANCER RESEARCH UK; C302/A24386

History

Publication status

  • Published

File Version

  • Published version

Journal

eLIfe

ISSN

2050-084X

Publisher

eLife Sciences Publications

Volume

8

Page range

1-28

Article number

a44353

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

2019-06-11

First Open Access (FOA) Date

2019-06-03

First Compliant Deposit (FCD) Date

2019-06-10

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