HUWE1 interacts with PCNA to alleviate replication stress
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 04, 2016
- Source ID
- 10.15252/embr.201541685
Entities
People
- Claudia M. Nicolae
- Daniel Constantin
- George-Lucian Moldovan
- Katherine N. Choe
- Maria Rocio Delgado‐diaz
- Raimundo Freire
- Subhajyoti De
- Veronique Aj Smits
- Yuka Imamura Kawasawa
Organizations
- American Cancer Society
- Colorado School of Public Health
- Concern Foundation
- Hospital Universitario de Canarias
- National Institutes of Health
- Pennsylvania State University
- University of Colorado