UBR5 interacts with the replication fork and protects DNA replication from DNA polymerase η toxicity.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
02 12 2019
02 12 2019
Historique:
accepted:
25
09
2019
revised:
06
09
2019
received:
13
02
2019
pubmed:
6
10
2019
medline:
2
6
2020
entrez:
6
10
2019
Statut:
ppublish
Résumé
Accurate DNA replication is critical for the maintenance of genome integrity and cellular survival. Cancer-associated alterations often involve key players of DNA replication and of the DNA damage-signalling cascade. Post-translational modifications play a fundamental role in coordinating replication and repair and central among them is ubiquitylation. We show that the E3 ligase UBR5 interacts with components of the replication fork, including the translesion synthesis (TLS) polymerase polη. Depletion of UBR5 leads to replication problems, such as slower S-phase progression, resulting in the accumulation of single stranded DNA. The effect of UBR5 knockdown is related to a mis-regulation in the pathway that controls the ubiquitylation of histone H2A (UbiH2A) and blocking this modification is sufficient to rescue the cells from replication problems. We show that the presence of polη is the main cause of replication defects and cell death when UBR5 is silenced. Finally, we unveil a novel interaction between polη and H2A suggesting that UbiH2A could be involved in polη recruitment to the chromatin and the regulation of TLS.
Identifiants
pubmed: 31586398
pii: 5581729
doi: 10.1093/nar/gkz824
pmc: PMC6868395
doi:
Substances chimiques
DNA, Single-Stranded
0
Histones
0
UBR5 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
DNA-Directed DNA Polymerase
EC 2.7.7.7
POLN protein, human
EC 2.7.7.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11268-11283Subventions
Organisme : Medical Research Council
ID : MR/N021002/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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