ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress.
Nat Commun
; 10(1): 5718, 2019 12 16.
Article
in En
| MEDLINE
| ID: mdl-31844045
ABSTRACT
Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2'-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proliferating Cell Nuclear Antigen
/
Genomic Instability
/
DNA-Binding Proteins
/
DNA Replication
/
Rad51 Recombinase
/
ATPases Associated with Diverse Cellular Activities
Limits:
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2019
Document type:
Article