RT Journal Article
T1 UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.
A1 Jachimowicz, Ron D
A1 Beleggia, Filippo
A1 Isensee, Jörg
A1 Velpula, Bhagya Bhavana
A1 Goergens, Jonas
A1 Bustos, Matias A
A1 Doll, Markus A
A1 Shenoy, Anjana
A1 Checa-Rodriguez, Cintia
A1 Wiederstein, Janica Lea
A1 Baranes-Bachar, Keren
A1 Bartenhagen, Christoph
A1 Hertwig, Falk
A1 Teper, Nizan
A1 Nishi, Tomohiko
A1 Schmitt, Anna
A1 Distelmaier, Felix
A1 Lüdecke, Hermann-Josef
A1 Albrecht, Beate
A1 Krüger, Marcus
A1 Schumacher, Björn
A1 Geiger, Tamar
A1 Hoon, Dave S B
A1 Huertas, Pablo
A1 Fischer, Matthias
A1 Hucho, Tim
A1 Peifer, Martin
A1 Ziv, Yael
A1 Reinhardt, H Christian
A1 Wieczorek, Dagmar
A1 Shiloh, Yosef
K1 DNA damage
K1 DNA double-strand break repair
K1 UBQLN4 deficiency syndrome
K1 cancer
K1 genome instability syndrome
K1 homologous recombination
K1 non-homologous end joining
K1 proteasomal degradation
K1 targeted cancer therapy
K1 ubiquitin
AB 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.
YR 2019
FD 2019-01-03
LK http://hdl.handle.net/10668/13378
UL http://hdl.handle.net/10668/13378
LA en
DS RISalud
RD Apr 5, 2025