title: UbcH7 regulates 53BP1 stability and DSB repair.
abstract: DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the error-prone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.
authors.affiliation: Department of Pharmacology.
authors.forename: Xiangzi
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pharmacology.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology.
authors.forename: Jinsil
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Pharmacology.
authors.forename: Franklin
authors.initials: F
authors.lastname: Mayca Pozo
authors.affiliation: Department of Pharmacology.
authors.forename: Amanda
authors.initials: A
authors.lastname: Tran
authors.affiliation: Department of Pharmacology.
authors.forename: Darcie D
authors.initials: DD
authors.lastname: Seachrist
authors.affiliation: Division of General Medical Sciences, Case Comprehensive Cancer Center, School of Medicine, and.
authors.forename: James W
authors.initials: JW
authors.lastname: Jacobberger
authors.affiliation: Department of Pharmacology.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Keri
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Hannah
authors.initials: H
authors.lastname: Gilmore
authors.affiliation: Department of Pharmacology, yxz169@case.edu.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D002166:Camptothecin / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D002166:Camptothecin
keywords: 53BP1; DNA damage response; DSB repair; UbcH7; protein degradation