English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/202874
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE
Exportar a otros formatos:

Title

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

AuthorsJachimowicz, Ron D.; Beleggia, Filippo; Isensee, Jörg; 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; Teper, Nizan; Nishi, Tomohiko; Schmitt, Anna; Distelmaier, Felix; Lüdecke, Hermann-Josef; Albrecht, Beate; Krüger, Markus; Schumacher, Björn; Geiger, Tamar; Hoon, Dave S.B.; Huertas Sánchez, Pablo CSIC ORCID; Fischer, Matthias; Hucho, Tim; Peifer, Martin; Ziv, Yael; Reinhardt, H. Christian; Wieczorek, Dagmar; Shiloh, Yosef
KeywordsDNA damage
DNA double-strand break repair
Homologous recombination
Non-homologous end joining
Cancer
Targeted cancer therapy
UBQLN4 deficiency syndrome
Genome instability syndrome
Ubiquitin
Proteasomal degradation
Issue Date24-Jan-2019
PublisherElsevier BV
CitationCell 176(3): 505-519.e22 (2019)
AbstractGenomic 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.cell.2018.11.024
URIhttp://hdl.handle.net/10261/202874
DOIhttp://dx.doi.org/10.1016/j.cell.2018.11.024
Identifiersdoi: 10.1016/j.cell.2018.11.024
e-issn: 1097-4172
issn: 0092-8674
Appears in Collections:(CABIMER) Artículos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.