HUWE1 interacts with PCNA to alleviate replication stress |
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| Authors: | Katherine N Choe Claudia M Nicolae Daniel Constantin Yuka Imamura Kawasawa Maria Rocio Delgado‐Diaz Subhajyoti De Raimundo Freire Veronique AJ Smits George‐Lucian Moldovan |
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| Institution: | 1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA;2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA;3. Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA;4. Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna, Tenerife, Spain;5. Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA;6. Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA;7. Molecular Oncology Program, University of Colorado Cancer Center, Aurora, CO, USA |
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| 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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| Keywords: | DNA replication genomic instability H2AX HUWE1
PCNA
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