Accumulation of nuclear p62, driven by loss of autophagy, decreases chromatin ubiquitination.

  • Major finding: Accumulation of nuclear p62, driven by loss of autophagy, decreases chromatin ubiquitination.

  • Mechanism: p62 inhibits RNF168 ligase activity to prevent the accumulation of DNA repair proteins at DSBs.

  • Impact: Selective autophagic degradation of p62 is critical for chromatin ubiquitination and DSB repair.

Recent studies have suggested that selective autophagy and the ubiquitin–proteasome system, which are the major protein degradation pathways in eukaryotic cells, participate in DNA double-strand break (DSB) repair. Further, selective autophagy of dysfunctional protein aggregates requires ubiquitination and the autophagic substrate and cargo receptor p62/sequestosome 1 (SQSTM1), which binds to ubiquitinated components in the cytosol, providing evidence of cross-talk between selective autophagy and the ubiquitin–proteasome system. To elucidate the mechanism underlying the role of autophagy in DSB repair and determine whether this mechanism is ubiquitination-dependent, Wang and colleagues assessed the effects of p62 on chromatin ubiquitination. Inhibition of autophagy resulted in the nuclear accumulation of p62, which subsequently inhibited chromatin and histone ubiquitination induced by ionizing radiation (IR)–mediated DNA damage. Nuclear p62 bound to the motif interacting with ubiquitin domain 1 (MIU1) domain in the E3 ligase ring finger protein 168 (RFN168), which has been implicated in DNA damage–induced ubiquitination, and inhibited RFN168 E3 ligase activity to prevent RNF168-mediated chromatin and histone ubiquitination. Binding of p62 to RNF168 inhibited the RNF168-mediated recruitment of homologous recombination (HR)–related DNA repair proteins–BRCA1, ubiquitin interaction motif containing 1 (RAP80, encoded by UIMC1), and RAD51–to DSBs, resulting in decreased HR-mediated DSB repair. Nuclear p62-expressing cells treated with IR exhibited impaired DNA repair kinetics and decreased growth in vitro and in vivo compared to p62-knockout cells or cells expressing cytoplasmic p62. Taken together, these results identify the mechanism underlying selective autophagy–driven DNA repair and show that nuclear p62 is critical for regulating DSB repair.

Wang Y, Zhang N, Zhang L, Li R, Fu W, Ma K, et al. Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62. Mol Cell 2016;63:34–48.

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