MassIVE MSV000098536

Partial Public PXD066219

SLFN11 counteracts the RFWD3-PRIMPOL DNA damage tolerance pathway to restrain gapped DNA synthesis in response to replication stress

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Description

Schlafen family member 11 (SLFN11) expression sensitizes cells to a spectrum of DNA-damaging chemotherapies. Previous studies have shown that SLFN11 is recruited to stalled replication forks in response to replication stress; however, the role of SLFN11 at stressed replication forks remains unclear. Using single-molecule DNA fiber analysis and super-resolution microscopy to interrogate the dynamics of individual replication forks, we show that SLFN11 acts upon stalled replication forks to suppress efficient fork restart. In the absence of SLFN11 expression, fork restart proceeds through a pathway involving the ubiquitin ligase RFWD3 and the DNA primase-polymerase PRIMPOL to facilitate gapped DNA synthesis. In the absence of SLFN11 expression, this pathway ensures that cells do not accumulate replication-associated DNA damage in response to stalled forks. Collectively, our results provide a mechanistic basis for how SLFN11 can counteract DNA damage tolerance by suppressing the RFWD3-PRIMPOL axis. The deposit includes the mass spectrometry data files generated from this study. [doi:10.25345/C5C824T1B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Schlafen-11, SLFN11, DNA synthesis, fork restart, PRIMPOL, RFWD3, fork-stalling, replication stress, hydroxyurea, DNA damage tolerance ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Beatrix M Ueberheide, NYU Langone Grossman School of Medicine, USA
Submitting User: KanshinED1
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