HUWE 1 interacts with PCNA to alleviate replication stress

KN Choe, CM Nicolae, D Constantin… - EMBO …, 2016 - embopress.org
KN Choe, CM Nicolae, D Constantin, Y Imamura Kawasawa, MR Delgado‐Diaz, S De
EMBO reports, 2016embopress.org
Defects in DNA replication, DNA damage response, and DNA repair compromise genomic
stability and promote cancer development. In particular, unrepaired DNA lesions can arrest
the progression of the DNA replication machinery during S‐phase, causing replication
stress, mutations, and DNA breaks. HUWE 1 is a HECT‐type ubiquitin ligase that targets
proteins involved in cell fate, survival, and differentiation. Here, we report that HUWE 1 is
essential for genomic stability, by promoting replication of damaged DNA. We show that …
Abstract
Defects in DNA replication, DNA damage response, and DNA repair compromise genomic stability and promote cancer development. In particular, unrepaired DNA lesions can arrest the progression of the DNA replication machinery during S‐phase, causing replication stress, mutations, and DNA breaks. HUWE1 is a HECT‐type ubiquitin ligase that targets proteins involved in cell fate, survival, and differentiation. Here, we report that HUWE1 is essential for genomic stability, by promoting replication of damaged DNA. We show that HUWE1‐knockout cells are unable to mitigate replication stress, resulting in replication defects and DNA breakage. Importantly, we find that this novel role of HUWE1 requires its interaction with the replication factor PCNA, a master regulator of replication fork restart, at stalled replication forks. Finally, we provide evidence that HUWE1 mono‐ubiquitinates H2AX to promote signaling at stalled forks. Altogether, our work identifies HUWE1 as a novel regulator of the replication stress response.
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