Perturbing cohesin dynamics drives MRE11 nuclease-dependent replication fork slowing.

Abstract:

: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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Carvajal-Maldonado D,Byrum AK,Jackson J,Wessel S,Lemaçon D,Guitton-Sert L,Quinet A,Tirman S,Graziano S,Masson JY,Cortez D,Gonzalo S,Mosammaparast N,Vindigni A

doi

10.1093/nar/gky519

subject

Has Abstract

pub_date

2019-02-20 00:00:00

pages

1294-1310

issue

3

eissn

0305-1048

issn

1362-4962

pii

5039657

journal_volume

47

pub_type

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