UBQLN4 Regulates DNA Repair Pathway Choice

The DNA damage response (DDR) is a signaling cascade primarily activated following induction of DNA double strand breaks (DSB) by the protein kinase ATM, which phosphorylates multiple substrates to activate the different branches of this vast network. In addition to protein phosphorylation, ubiquitination also occurs at DSB sites, but few ubiquitinated proteins have been identified and the role of this post-translational modification in the DDR is less clear. Jachimowicz and colleagues identified a homozygous germline mutation in ubiquilin 4 (UBQLN4), a gene encoding a protein that shuttles ubiquitinated proteins to the proteasome for degradation, in families with an autosomal recessive syndrome with similar clinical manifestations as disorders caused by mutations in DDR genes, suggesting that UBQLN4 may play a role in this process. Consistent with this possibility, UBQLN4-mutant and UBQLN4-deficient cells were hypersensitive to genotoxic agents, and UBQLN4 loss significantly delayed clearance nuclear foci representing unrepaired DSBs. Furthermore, UBQLN4 was shown to be an ATM substrate, and ATM-dependent phosphorylation of UBQLN4 was required for proper DSB repair. Following DSB induction, UBQLN4 interacted with the nuclease MRE11, which normally initiates DSB repair by binding and resecting DSB ends. UBQLN4 bound ubiquitinated MRE11 and promoted its removal from damaged chromatin. The presence of UBQLN4 dictated whether cells used homologous recombination-mediated DNA repair (HRR) or nonhomologous end-joining (NHEJ) to repair DSBs, as loss of UBQLN4 increased HRR pathway usage in response to DNA damage and UBQLN4 overexpression led to a significant increase in NHEJ usage relative to HRR. HRR deficiency is a known biomarker of sensitivity to PARP inhibition, and UBQLN4 overexpression, which is observed in a number of human cancers and associated with poor outcome, conferred sensitivity to the PARP inhibitor olaparib in vitro. HRR deficiency caused by UBQLN4 overexpression and increased MRE11 turnover may therefore be actionable and potentially expand the number of tumors for which PARP inhibitors might be effective.

Jachimowicz RD, Beleggia F, Isensee J, Bhavana Velpula B, Goergens J, Bustos MA, et al. UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors. Cell 2019 Jan 3 [Epub ahead of print].

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