Perturbing cohesin dynamics drives MRE11 nuclease-dependent replication fork slowing.
BRCA2 Protein
/ genetics
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
Chromatids
/ genetics
Chromosomal Proteins, Non-Histone
/ genetics
DNA Damage
/ genetics
DNA Replication
/ genetics
DNA-Binding Proteins
Deoxyribonucleases
/ genetics
Humans
MRE11 Homologue Protein
/ genetics
Nuclear Proteins
/ genetics
Phosphoproteins
/ genetics
Sister Chromatid Exchange
/ genetics
Cohesins
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
20 02 2019
20 02 2019
Historique:
accepted:
25
05
2018
revised:
22
05
2018
received:
26
01
2018
pubmed:
20
6
2018
medline:
21
8
2019
entrez:
20
6
2018
Statut:
ppublish
Résumé
Pds5 is required for sister chromatid cohesion, and somewhat paradoxically, to remove cohesin from chromosomes. We found that Pds5 plays a critical role during DNA replication that is distinct from its previously known functions. Loss of Pds5 hinders replication fork progression in unperturbed human and mouse cells. Inhibition of MRE11 nuclease activity restores fork progression, suggesting that Pds5 protects forks from MRE11-activity. Loss of Pds5 also leads to double-strand breaks, which are again reduced by MRE11 inhibition. The replication function of Pds5 is independent of its previously reported interaction with BRCA2. Unlike Pds5, BRCA2 protects forks from nucleolytic degradation only in the presence of genotoxic stress. Moreover, our iPOND analysis shows that the loading of Pds5 and other cohesion factors on replication forks is not affected by the BRCA2 status. Pds5 role in DNA replication is shared by the other cohesin-removal factor Wapl, but not by the cohesin complex component Rad21. Interestingly, depletion of Rad21 in a Pds5-deficient background rescues the phenotype observed upon Pds5 depletion alone. These findings support a model where loss of either component of the cohesin releasin complex perturbs cohesin dynamics on replication forks, hindering fork progression and promoting MRE11-dependent fork slowing.
Identifiants
pubmed: 29917110
pii: 5039657
doi: 10.1093/nar/gky519
pmc: PMC6379725
doi:
Substances chimiques
BRCA2 Protein
0
Cell Cycle Proteins
0
Chromosomal Proteins, Non-Histone
0
DNA-Binding Proteins
0
MRE11 protein, human
0
Nuclear Proteins
0
PDS5A protein, human
0
Phosphoproteins
0
RAD21 protein, human
0
Deoxyribonucleases
EC 3.1.-
MRE11 Homologue Protein
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
1294-1310Subventions
Organisme : NIA NIH HHS
ID : R01 AG058714
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM108648
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM116616
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193318
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM094513
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NIGMS NIH HHS
ID : T32 GM008306
Pays : United States
Informations de copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
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