Jachimowicz, Ron D., Beleggia, Filippo ORCID: 0000-0003-0234-7094, Isensee, Joerg ORCID: 0000-0002-3390-0051, Velpula, Bhagya Bhavana, Goergens, Jonas, Bustos, Matias A., Doll, Markus A., Shenoy, Anjana, Checa-Rodriguez, Cintia, Wiederstein, Janica Lea, Baranes-Bachar, Keren, Bartenhagen, Christoph, Hertwig, Falk ORCID: 0000-0003-4784-6516, Teper, Nizan, Nishi, Tomohiko, Schmitt, Anna, Distelmaier, Felix, Luedecke, Hermann-Josef, Albrecht, Beate, Krueger, Marcus ORCID: 0000-0003-2008-4582, Schumacher, Bjorn ORCID: 0000-0001-6097-5238, Geiger, Tamar, Hoon, Dave S. B., Huertas, Pablo ORCID: 0000-0002-1756-4449, Fischer, Matthias, Hucho, Tim, Peifer, Martin, Ziv, Yael, Reinhardt, H. Christian, Wieczorek, Dagmar and Shiloh, Yosef (2019). UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell, 176 (3). S. 505 - 542. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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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 windowfor PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Jachimowicz, Ron D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Isensee, JoergUNSPECIFIEDorcid.org/0000-0002-3390-0051UNSPECIFIED
Velpula, Bhagya BhavanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bustos, Matias A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doll, Markus A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shenoy, AnjanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Checa-Rodriguez, CintiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiederstein, Janica LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baranes-Bachar, KerenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertwig, FalkUNSPECIFIEDorcid.org/0000-0003-4784-6516UNSPECIFIED
Teper, NizanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nishi, TomohikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Distelmaier, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luedecke, Hermann-JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albrecht, BeateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDorcid.org/0000-0003-2008-4582UNSPECIFIED
Schumacher, BjornUNSPECIFIEDorcid.org/0000-0001-6097-5238UNSPECIFIED
Geiger, TamarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoon, Dave S. B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huertas, PabloUNSPECIFIEDorcid.org/0000-0002-1756-4449UNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziv, YaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shiloh, YosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-158923
DOI: 10.1016/j.cell.2018.11.024
Journal or Publication Title: Cell
Volume: 176
Number: 3
Page Range: S. 505 - 542
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; CELLULAR-RESPONSE; REPAIR; PROTEINS; PROTEASOME; PATHWAYS; ATMMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15892

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