CECAD Microsite

Christian Reinhardt Lab

Ron Jachimowicz’s paper regarding “UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors” - published in Cell.


Jachimowicz et al. identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 loss leads to increased sensitivity to genotoxic stress and delayed double-strand break (DSB) repair. Moreover, ATM-dependent S318-UBQLN4 phosphorylation is required for DSB repair. He and his colleges demonstrate that UBQLN4 interacts with ubiquitylated MRE11, which mediates early steps of homologousrecombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, driving non-physiological HRR. Concomitantly, UBQLN4 depletion is associated with increased HRR activity in vitro and in vivo. Conversely, UBQLN4 over-expression represses HRR and favors non-homologous end joining. Moreover, Jachimowicz et al. find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in such entities, they observe that UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. Altogether, UBQLN4 curtails HRR activity through removal of MRE11 from damaged chromatin, and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4 over-expressing tumors.