Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Bigot, Nicolas, Day, Matthew, Baldock, Robert A, Watts, Felicity Z, Oliver, Antony W, Pearl, Laurence H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561707/
https://www.ncbi.nlm.nih.gov/pubmed/31135337
http://dx.doi.org/10.7554/eLife.44353
_version_ 1783426176605224960
author Bigot, Nicolas
Day, Matthew
Baldock, Robert A
Watts, Felicity Z
Oliver, Antony W
Pearl, Laurence H
author_facet Bigot, Nicolas
Day, Matthew
Baldock, Robert A
Watts, Felicity Z
Oliver, Antony W
Pearl, Laurence H
author_sort Bigot, Nicolas
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6561707
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-65617072019-06-13 Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint Bigot, Nicolas Day, Matthew Baldock, Robert A Watts, Felicity Z Oliver, Antony W Pearl, Laurence H eLife Cell Biology 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. eLife Sciences Publications, Ltd 2019-05-28 /pmc/articles/PMC6561707/ /pubmed/31135337 http://dx.doi.org/10.7554/eLife.44353 Text en © 2019, Bigot et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Bigot, Nicolas
Day, Matthew
Baldock, Robert A
Watts, Felicity Z
Oliver, Antony W
Pearl, Laurence H
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title_full Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title_fullStr Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title_full_unstemmed Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title_short Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
title_sort phosphorylation-mediated interactions with topbp1 couple 53bp1 and 9-1-1 to control the g1 dna damage checkpoint
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561707/
https://www.ncbi.nlm.nih.gov/pubmed/31135337
http://dx.doi.org/10.7554/eLife.44353
work_keys_str_mv AT bigotnicolas phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint
AT daymatthew phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint
AT baldockroberta phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint
AT wattsfelicityz phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint
AT oliverantonyw phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint
AT pearllaurenceh phosphorylationmediatedinteractionswithtopbp1couple53bp1and911tocontroltheg1dnadamagecheckpoint