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Autophagy substrate SQSTM1/p62 regulates chromatin ubiquitination during the DNA damage response

Yanan Wang1, Wei-Guo Zhu1,2,3, Ying Zhao1

  • 1a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function , Department of Biochemistry and Molecular Biology , School of Basic Medical Sciences, Peking University Health Science Center , Beijing , China.

Autophagy
|October 30, 2016
PubMed

Insights

Autophagy deficiency impairs DNA repair by preventing histone ubiquitination via SQSTM1/p62, increasing radiation sensitivity. This reveals a novel role for autophagy in maintaining genomic stability.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Autophagy is crucial for DNA damage repair, but its precise molecular mechanisms remain unclear.
  • Histone ubiquitination is a key event in DNA damage response pathways.

Purpose of the Study:

  • To elucidate the molecular mechanism linking autophagy to DNA damage repair.
  • To investigate the role of SQSTM1/p62 in regulating histone ubiquitination during DNA damage response.

Main Methods:

  • Cellular assays to assess DNA damage repair efficiency in autophagy-deficient cells.
  • Immunoblotting and immunoprecipitation to analyze histone H2A ubiquitination and SQSTM1/p62 interactions.
  • Assessment of DNA double-strand break (DSB) repair factor recruitment.

Main Results:

  • DNA damage-induced histone H2A ubiquitination is significantly suppressed in autophagy-deficient cells.
  • SQSTM1/p62 directly binds to and inhibits the E3 ligase RNF168, which is essential for H2A ubiquitination.
  • Autophagy deficiency leads to impaired recruitment of DNA repair factors to DSBs, resulting in reduced repair and increased sensitivity to radiation.

Conclusions:

  • SQSTM1/p62-mediated inhibition of RNF168 is a critical mechanism by which autophagy influences DNA repair.
  • Autophagy plays a vital role in maintaining genomic stability through the regulation of histone ubiquitination and DNA repair factor recruitment.
Keywords:
DNA damageRNF168autophagyhistone ubiquitinationp62

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