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Cell. 2019 Jan 24;176(3):505-519.e22. doi: 10.1016/j.cell.2018.11.024. Epub 2019 Jan 3.

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.

Author information

1
The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany. Electronic address: ron.jachimowicz@uk-koeln.de.
2
Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany; Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany.
3
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital Cologne, Cologne 50931, Germany.
4
The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
5
Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany.
6
Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
7
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Institute for Genome Stability in Aging, Cologne, Germany.
8
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
9
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide and Department of Genetics, University of Sevilla, Sevilla 41092, Spain.
10
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
11
Department of Experimental Pediatric Oncology, University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
12
Department of Pediatric Oncology and Hematology, Charité, Berlin, Germany; German Cancer Consortium, Germany; Berlin Institute of Health, Germany.
13
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Hospital, Heinrich-Heine-University, Düsseldorf 40225, Germany.
14
Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany; Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany.
15
Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany.
16
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
17
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department of Translational Genomics, University of Cologne, Cologne, Germany.
18
The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yaelz@post.tau.ac.il.
19
Clinic I of Internal Medicine, University Hospital Cologne, Cologne 50931, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. Electronic address: christian.reinhardt@uk-koeln.de.
20
Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany; Institute of Human Genetics, University Clinic Duisburg-Essen, Essen, Germany. Electronic address: dagmar.wieczorek@hhu.de.
21
The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: yossih@post.tau.ac.il.

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.

KEYWORDS:

DNA damage; DNA double-strand break repair; UBQLN4 deficiency syndrome; cancer; genome instability syndrome; homologous recombination; non-homologous end joining; proteasomal degradation; targeted cancer therapy; ubiquitin

PMID:
30612738
DOI:
10.1016/j.cell.2018.11.024

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