Beta human papillomavirus 8E6 promotes alternative end joining.

Autor:	Hu C; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.; Division of Biology, Kansas State University, Manhattan, United States., Bugbee T; Division of Biology, Kansas State University, Manhattan, United States., Palinski R; Veterinary Diagnostic Laboratory, Kansas State University, Manhattan, United States., Akinyemi IA; Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, United States.; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, United States., McIntosh MT; Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, United States., MacCarthy T; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, United States., Bhaduri-McIntosh S; Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, United States.; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, United States., Wallace N; Division of Biology, Kansas State University, Manhattan, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Jan 24; Vol. 12. Date of Electronic Publication: 2023 Jan 24.
DOI:	10.7554/eLife.81923
Abstrakt:	Double strand breaks (DSBs) are one of the most lethal DNA lesions in cells. The E6 protein of beta-human papillomavirus (HPV8 E6) impairs two critical DSB repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). However, HPV8 E6 only delays DSB repair. How DSBs are repaired in cells with HPV8 E6 remains to be studied. We hypothesize that HPV8 E6 promotes a less commonly used DSB repair pathway, alternative end joining (Alt-EJ). Using CAS9-based Alt-EJ reporters, we show that HPV8 E6 promotes Alt-EJ. Further, using small molecule inhibitors, CRISPR/CAS9 gene knockout, and HPV8 E6 mutant, we find that HPV8 E6 promotes Alt-EJ by binding p300, an acetyltransferase that facilitates DSB repair by HR and NHEJ. At least some of this repair occurs through a subset of Alt-EJ known as polymerase theta dependent end joining. Finally, whole genome sequencing analysis showed HPV8 E6 caused an increased frequency of deletions bearing the microhomology signatures of Alt-EJ. This study fills the knowledge gap of how DSB is repaired in cells with HPV8 E6 and the mutagenic consequences of HPV8 E6 mediated p300 destabilization. Broadly, this study supports the hypothesis that beta-HPV promotes cancer formation by increasing genomic instability. Competing Interests: CH, TB, RP, IA, MM, TM, SB, NW No competing interests declared (© 2023, Hu et al.)
Databáze:	MEDLINE
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