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

Bigot, Nicolas, Day, Matthew, Baldock, Robbie A, Watts, Felicity Z, Oliver, Antony W and Pearl, Laurence H (2019) Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint. eLIfe. ISSN 2050-084X

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Abstract

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.

Item Type: Article
Keywords: DNA Repair, Checkpoint signalling, DNA damage response
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Laurence Pearl
Date Deposited: 11 Jun 2019 07:41
Last Modified: 13 Aug 2019 15:25
URI: http://sro.sussex.ac.uk/id/eprint/84221

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Project NameSussex Project NumberFunderFunder Ref
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug DiscoveryUnsetCancer Research UKC302/A14532
Structural Biology of DNA Damage Response and Repair MechanismsUnsetCANCER RESEARCH UKC302/A24386