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Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks.

Abstract：

:Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2Ct, the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2Ct constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation. The Arg/N-end rule and VCP/p97UFD1-NPL4 segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2Ct degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2Ct, fail to induce RPA phosphorylation and single-stranded DNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery. Together, our study elucidates a previously unappreciated axis connecting the Arg/N-end rule and the p97-mediated proteolysis with the replication stress response, working together to preserve replication fork integrity.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Rageul J,Park JJ,Jo U,Weinheimer AS,Vu TTM,Kim H

doi

10.1093/nar/gkz054

subject

Has Abstract

pub_date

2019-05-07 00:00:00

pages

3996-4010

issue

8

eissn

0305-1048

issn

1362-4962

pii

5304317

journal_volume

47

pub_type

杂志文章

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