Hrq1/RECQL4 regulation is critical for preventing aberrant recombination during DNA intrastrand crosslink repair and is upregulated in breast cancer
Abstract
Human RECQL4 is a member of the RecQ family of DNA helicases and functions during DNA replication and repair.RECQL4mutations are associated with developmental defects and cancer. AlthoughRECQL4mutations lead to disease,RECQL4overexpression is also observed in cancer, including breast and prostate. Thus, tight regulation of RECQL4 protein levels is crucial for genome stability. Because mammalianRECQL4is essential, how cells regulate RECQL4 protein levels is largely unknown. Utilizing budding yeast, we investigated theRECQL4homolog,HRQ1, during DNA crosslink repair. We find that Hrq1 functions in the error-free template switching pathway to mediate DNA intrastrand crosslink repair. Although Hrq1 mediates repair of cisplatin-induced lesions, it is paradoxically degraded by the proteasome following cisplatin treatment. By identifying the targeted lysine residues, we show that preventing Hrq1 degradation results in increased recombination and mutagenesis. Like yeast, human RECQL4 is similarly degraded upon exposure to crosslinking agents. Furthermore, over-expression ofRECQL4results in increased RAD51 foci, which is dependent on its helicase activity. Using bioinformatic analysis, we observe thatRECQL4overexpression correlates with increased recombination and mutations. Overall, our study uncovers a role for Hrq1/RECQL4 in DNA intrastrand crosslink repair and provides further insight how misregulation of RECQL4 can promote genomic instability, a cancer hallmark.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 20, 2022
- Source ID
- 10.1371/journal.pgen.1010122
Entities
People
- Adrian V Lee
- Kara A. Bernstein
- Kyle Rapchak
- Nolan Priedigkeit
- Phoebe S. Parker
- Stefanie Böhm
- Thong T. Luong
- Zheqi Li
Organizations
- National Institute of Environmental Health Sciences
- United States Department of Defense