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SLFN11 Blocks Stressed Replication Forks Independently of ATR.

Authors :
Murai J
Tang SW
Leo E
Baechler SA
Redon CE
Zhang H
Al Abo M
Rajapakse VN
Nakamura E
Jenkins LMM
Aladjem MI
Pommier Y
Source :
Molecular cell [Mol Cell] 2018 Feb 01; Vol. 69 (3), pp. 371-384.e6.
Publication Year :
2018

Abstract

SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.<br /> (Published by Elsevier Inc.)

Details

Language :
English
ISSN :
1097-4164
Volume :
69
Issue :
3
Database :
MEDLINE
Journal :
Molecular cell
Publication Type :
Academic Journal
Accession number :
29395061
Full Text :
https://doi.org/10.1016/j.molcel.2018.01.012