title: USP28 is recruited to sites of DNA damage by the tandem BRCT domains of 53BP1 but plays a minor role in double-strand break metabolism.
abstract: The DNA damage response (DDR) is critical for genome stability and the suppression of a wide variety of human malignancies, including neurodevelopmental disorders, immunodeficiency, and cancer. In addition, the efficacy of many chemotherapeutic strategies is dictated by the status of the DDR. Ubiquitin-specific protease 28 (USP28) was reported to govern the stability of multiple factors that are critical for diverse aspects of the DDR. Here, we examined the effects of USP28 depletion on the DDR in cells and in vivo. We found that USP28 is recruited to double-strand breaks in a manner that requires the tandem BRCT domains of the DDR protein 53BP1. However, we observed only minor DDR defects in USP28-depleted cells, and mice lacking USP28 showed normal longevity, immunological development, and radiation responses. Our results thus indicate that USP28 is not a critical factor in double-strand break metabolism and is unlikely to be an attractive target for therapeutic intervention aimed at chemotherapy sensitization.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Knobel
authors.forename: Rimma
authors.initials: R
authors.lastname: Belotserkovskaya
authors.forename: Yaron
authors.initials: Y
authors.lastname: Galanty
authors.forename: Christine K
authors.initials: CK
authors.lastname: Schmidt
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D060168:Thymocytes / Q000276:immunology; D000071857:Tumor Suppressor p53-Binding Protein 1; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C442902:USP28 protein, human; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse; D043222:Ubiquitin Thiolesterase