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DCAF14 promotes stalled fork stability to maintain genome integrity

Replication stress response ensures impediments to DNA replication do not compromise replication fork stability and genome integrity. In a process termed replication fork protection, newly synthesized DNA at stalled replication forks is stabilized and protected from nuclease-mediated degradation. We...

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Published in:Cell reports (Cambridge) 2021-01, Vol.34 (4), p.108669-108669, Article 108669
Main Authors: Townsend, Arik, Lora, Gabriella, Engel, Justin, Tirado-Class, Neysha, Dungrawala, Huzefa
Format: Article
Language:English
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Summary:Replication stress response ensures impediments to DNA replication do not compromise replication fork stability and genome integrity. In a process termed replication fork protection, newly synthesized DNA at stalled replication forks is stabilized and protected from nuclease-mediated degradation. We report the identification of DDB1- and CUL4-associated factor 14 (DCAF14), a substrate receptor for Cullin4-RING E3 ligase (CRL4) complex, integral in stabilizing stalled replication forks. DCAF14 localizes rapidly to stalled forks and promotes genome integrity by preventing fork collapse into double-strand breaks (DSBs). Importantly, CRL4DCAF14 mediates stalled fork protection in a RAD51-dependent manner to protect nascent DNA from MRE11 and DNA2 nucleases. Thus, our study shows replication stress response functions of DCAF14 in genome maintenance. [Display omitted] •DCAF14 is enriched at stalled replication forks•DDB1, CUL4B, and DCAF14 facilitate stalled fork stability•DCAF14 suppresses DNA2- and MRE11-mediated nascent strand degradation•DCAF14 promotes replication fork protection in a RAD51-dependent manner Townsend et al. find that DDB1- and CUL4-associated factor DCAF14 is recruited to stalled replication forks. DCAF14 prevents replication fork collapse in a CRL4-dependent manner to promote genome stability and cell survival. DCAF14 depletion triggers nascent strand degradation that is reversible by enhancing RAD51 levels at forks.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108669