title: RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation.
abstract: Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Kiran Kumar Naidu
authors: KKN
authors: Guturi
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Miyuki
authors: M
authors: Bohgaki
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Toshiyuki
authors: T
authors: Bohgaki
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Tharan
authors: http://orcid.org/0000-0003-3359-0281
authors: T
authors: Srikumar
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Deborah
authors: D
authors: Ng
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Ramya
authors: R
authors: Kumareswaran
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Samah
authors: S
authors: El Ghamrasni
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Justin
authors: J
authors: Jeon
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Parasvi
authors: P
authors: Patel
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Mohamed Saad
authors: MS
authors: Eldin
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Rob
authors: R
authors: Bristow
authors: Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.
authors: Peter
authors: P
authors: Cheung
authors: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors: Grant S
authors: GS
authors: Stewart
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Brian
authors: B
authors: Raught
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Anne
authors: A
authors: Hakem
authors: Department of Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Razqallah
authors: R
authors: Hakem
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D020090:Chromosome Segregation / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D043864:DNA, Catenated / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007859:Learning Disabilities / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000081207:Primary Immunodeficiency Diseases; D040901:Proteomics; D034741:RNA, Small Interfering / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D043864:DNA, Catenated; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; D059005:Topoisomerase II Inhibitors; C431363:USP10 protein, human; C579090:USP10 protein, mouse; D005047:Etoposide; C535210:RNF168 protein, human; C579124:RNF168 protein, mouse; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse