HUWE1 Interacts with PCNA to Alleviate Replication Stress
Open Access
- Author:
- Choe, Katherine Naeun
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 22, 2016
- Committee Members:
- George Lucian Moldovan, Dissertation Advisor/Co-Advisor
George Lucian Moldovan, Committee Chair/Co-Chair
James Riley Broach, Committee Member
Ralph Lauren Keil, Committee Member
Kent Eugene Vrana, Outside Member
Cristina I Truica, Special Member - Keywords:
- DNA replication
Genomic instability
H2AX
DNA Damage
HUWE1
PCNA
Replication stress - Abstract:
- The integrity of the genome relies on the accurate and faithful duplication of genetic information from a parental cell to its progeny during each cellular division. Defects in DNA replication, DNA damage response, or DNA repair compromise genomic stability and promote cancer development as well as other diseases. 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 monoubiquitinates H2AX to promote signaling at stalled forks. Altogether, our work identifies HUWE1 as a novel regulator of the replication stress response.