eLife.44353_corrected_proofs.pdf (10.94 MB)
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
Version 2 2023-06-12, 09:08
Version 1 2023-06-09, 18:02
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 PearlCoordination 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
eLIfeISSN
2050-084XPublisher
eLife Sciences PublicationsExternal DOI
Volume
8Page range
1-28Article number
a44353Department 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
2019-06-11First Open Access (FOA) Date
2019-06-03First Compliant Deposit (FCD) Date
2019-06-10Usage metrics
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