UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Abstract

Graphical Abstract Highlights d Homozygous UBQLN4 germline mutations lead to a genome instability syndrome d UBQLN4 removes ubiquitylated MRE11 from damaged chromatin to curtail DSB resection d UBQLN4 overexpression represses HRR and promotes the use of NHEJ for DSB repair d UBQLN4 overexpression in tumors promotes PARP1 inhibitor sensitivity SUMMARY 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 UBQLN4overexpressing tumors.of selected pairs defined in a contrast matrix using the R library multcomp. Error bars represent SD of the mean for 3 replicate wells analyzed in one experiment. Each experiment was carried out twice. *p < 0.05. (N) Quantification of the relative comet tail moment (n = 100) derived from the neutral comet assays at the indicated time points. Error bars represent SD of the mean of the relative comet tail moment analyzed in n = 3 experiments.

UBQLN4 promotes non-homologous end joining by repressing DNA end-resection

“…6 In affected patients, as well as in C. elegans ubql-1 mutants, the nematode ortholog of UBQLN4, we observed an increase of HR usage, fully in line with a functional defect of UBQLN4-mediated MRE11 turnover. 6 In healthy individuals, overt accumulation of ubiquitylated MRE11 on damaged chromatin is prevented by UBQLN4. Intriguingly, the interaction of MRE11 and UBQLN4 is regulated by ATM.…”

“…6 We found that the proteasomal shuttle factor UBQLN4 binds to ubiquitylated MRE11 via its Ubiquitin-associated (UBA) domain and promotes its degradation, thus limiting the initiation of DNA end resection. 6 In affected patients, as well as in C. elegans ubql-1 mutants, the nematode ortholog of UBQLN4, we observed an increase of HR usage, fully in line with a functional defect of UBQLN4-mediated MRE11 turnover. 6 In healthy individuals, overt accumulation of ubiquitylated MRE11 on damaged chromatin is prevented by UBQLN4.…”

DNA damage kinase signaling: checkpoint and repair at 30 years

“…This process is achieved through a defined order of events: phosphorylation of H2AX and MDC1, followed by recruitment of the RNF8 and RNF168 ubiquitin ligases, followed by ubiquitylation of H2A and recruitment of 53BP1, whose phosphorylation by ATM serves as a docking platform for RIF1 and, indirectly, the REV7–SHIELDIN complex (Fig ). In addition, ATM limits resection by phosphorylating the proteasomal shuttle factor UBQLN4, which leads to degradation of MRE11, a component of the MRN complex required for initial steps in resection (Jachimowicz et al , ). Paradoxically, ATM may also promote resection by phosphorylating CtIP, a key factor required for resection initiation (Shibata et al , ).…”

UBQLN4 promotes progression of HCC via activating wnt-β-catenin pathway and is regulated by miR-370

“…Ubiquilin -2 is involved in migration and invasion of breast cancer [10] and lung cancer cells [11]. A recent study showed that UBQLN4 could curtail HRR activity by removing MRE11 from damaged chromatin and provide a therapeutic target for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors [12]. Ubiquilin -4 acts as a tumor suppressor during the progression of gastric cancer by inducing cell cycle arrest and senescence via the extracellular signal-regulated kinases (ERK) signaling pathway [13,14].…”