1. UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
- Author
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Martin Peifer, F Hertwig, Jonas Goergens, Tamar Geiger, Yael Ziv, Filippo Beleggia, Dagmar Wieczorek, Felix Distelmaier, Beate Albrecht, Pablo Huertas, Matthias Fischer, Anjana Shenoy, Björn Schumacher, Markus A. Doll, Janica L Wiederstein, Marcus Krüger, Yosef Shiloh, Dave S.B. Hoon, Cintia Checa-Rodríguez, H. Christian Reinhardt, Jörg Isensee, Anna Schmitt, Matias A. Bustos, Bhagya Bhavana Velpula, Tim Hucho, Ron D. Jachimowicz, Tomohiko Nishi, Nizan Teper, Christoph Bartenhagen, Hermann-Josef Lüdecke, Keren Baranes-Bachar, Adelson Medical Research Foundation, Israel Science Foundation, Israel Cancer Research Fund, German-Israeli Foundation for Scientific Research and Development, German Research Foundation, Else Kröner-Fresenius Foundation, Deutsche Krebshilfe, Federal Ministry of Education and Research (Germany), Ministerio de Economía y Competitividad (España), and Universidad de Sevilla. Departamento de Genética
- Subjects
Male ,Genome instability ,DNA End-Joining Repair ,DNA damage ,Primary Cell Culture ,Medizin ,medicine.disease_cause ,Genomic Instability ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Proteasomal degradation ,0302 clinical medicine ,PARP1 ,Ubiquitin ,Neoplasms ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Targeted cancer therapy ,Homologous recombination ,Germ-Line Mutation ,Cancer ,030304 developmental biology ,MRE11 Homologue Protein ,0303 health sciences ,Mutation ,biology ,Genome instability syndrome ,Nuclear Proteins ,Recombinational DNA Repair ,DNA double-strand break repair ,DNA ,UBQLN4 deficiency syndrome ,Chromatin ,DNA-Binding Proteins ,Non-homologous end joining ,enzymes and coenzymes (carbohydrates) ,Cancer research ,biology.protein ,Female ,Carrier Proteins ,human activities ,030217 neurology & neurosurgery - Abstract
Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.Control of MRE11 association with chromatin by UBQLN4 during double-strand break repair influences repair pathway choice and can be dysregulated in tumorigenesis., This work was funded through the Dr. M. and S.G. Adelson Medical Research Foundation, The Israel Science Foundation joint ISF-NSFC Research Program and The Israel Cancer Research Fund (to Y.S.), the German-Israeli Foundation for Research and Development (I-65-412.20-2016 to Y.S. and H.C.R.), the Deutsche Forschungsgemeinschaft (KFO-286-RP2 to H.C.R., KFO-286-CP2 to M.P., JA2439/1-1 to R.D.J., DI1731/2-1 to F.D.), the Else Kröner-Fresenius Stiftung (2014-A06 to H.C.R., 2016_Kolleg.19 to R.D.J.), the Deutsche Krebshilfe (1117240 to H.C.R. and the Mildred-Scheel Professorship to M.P.), the German Ministry of Education and Research (BMBF 01GM1211B to D.W., BMBF e:Med 01ZX1303A and 01ZX1406 to M.P., BMBF e:Med 01ZX1303 and 01ZX1307 to M.F.), and R+D+I grants from the Spanish Ministry of Economy and Competitivity (SAF2013-43255-P and SAF2016-74855-P to P.H.). Y.S. is a Research Professor of the Israel Cancer Research Fund.
- Published
- 2019
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