Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62

Abstract

Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced histone H2A ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for histone H2A ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair. Moreover, nuclear-localized p62 increased the sensitivity of tumor cells to radiation both in vitro and in vivo, and this required its interaction with RNF168. Our findings indicate that autophagy-deficiency-induced p62 accumulation results in inhibition of histone ubiquitination and highlight the complex relationship between autophagy and the DNA damage response.

p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

“…Through the ability of p62 to interact with TRAF6, p62 activates NF-κB (14). Recently, p62 has been shown to promote genomic instability by slowing the repair of DNA double strand breaks, thereby promoting error prone nonhomologous end joining (NHEJ) (15). p62 also sequesters Keap1 from Nrf2 and promotes activation of the antioxidant transcription pathway (16–18), while also acting as a direct positive regulator of mTORC1 through interactions with Raptor and the Rag proteins in the amino acid-sensing pathway (19,20).…”

Autophagy regulates DNA repair through SQSTM1/p62

“…1 An analysis of chromatin protein extracted from HeLa cells, revealed that SQSTM1 knockdown increases chromatin poly-ubiquitination. Conversely, overexpression of SQSTM1 has the opposite effect, reducing this DNA-damage-induced chromatin ubiquitination.…”

Autophagy regulates DNA repair by modulating histone ubiquitination

“…In addition, in the absence of autophagy IR failed to induce RNF168, BRCA1, RAP80, and Rad51 foci formation; however, the foci were recovered in p62 knockdown cells. These observations indicate that p62 is a physiologic modulator of DNA repair 9 (Fig. 1).…”