UBQLN4, a regulator of protein dynamics at sites of DNA damage, is lost in a new genome instability syndrome and elevated in aggressive tumors

ABSTRACT: The ubiquitin-proteasome system (UPS) plays a crucial role in cellular homeostasis, but the mechanistic aspects of its involvement in the DNA damage response (DDR) remain largely elusive. Here, we identify a homozygous truncation mutation in the UBQLN4 gene in families with highly pleiotropic autosomal recessive syndrome, with clinical and cellular characteristics reminiscent of DNA repair disorders. UBQLN4 loss leads to hypersensitivity to genotoxic stress and delayed repair of DNA double-strand breaks (DSBs). By dissecting the molecular mechanism of action, we find an ATM-dependent phosphorylation site on UBQLN4 (Ser-318), which is required for the cellular protection against DNA damage and proper DSB repair. UBQLN4 is a known proteasomal shuttle factor for ubiquitinated proteins and we demonstrate that loss of UBQLN4 leads to the accumulation and retention of MRE11 and RPA70 at DSB sites. Concomitantly, we find that UBQLN4 loss of function is associated with a relative increase in homologous recombination-mediated DSB repair and a reduced usage of non-homologous end joining. In contrast, UBQLN4 overexpression represses HRR usage. We show that this UBQLN4-driven preference for NHEJ-mediated DSB repair is conserved in C. elegans. Moreover, a detailed analysis of human neuroblastoma and melanoma cancer samples reveals that UBQLN4 is overexpressed in aggressive tumors. In line with a HRR defect, we observe that tumor cells overexpressing UBQLN4 display an actionable PARP1 inhibitor sensitivity. Thus, we identify a novel DDR component, which may be a promising target for PARP1 inhibition in aggressive cancer. 

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Tamar Geiger  

LAB HEAD: Tamar Geiger

PROVIDER: PXD008299 | Pride | 2020-06-02

REPOSITORIES: Pride