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Chfr and RNF8 synergistically regulate ATM activation

Jiaxue Wu1, Yibin Chen, Lin-Yu Lu

  • 1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Nature Structural & Molecular Biology
|June 28, 2011
PubMed

Insights

RNF8 and Chfr E3 ligases are crucial for DNA damage response. Their combined loss suppresses ATM activation, leading to genomic instability and cancer in mice.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Protein ubiquitination is vital for DNA damage response.
  • E3 ubiquitin ligases play key roles in this process.

Purpose of the Study:

  • To investigate the roles of RNF8 and Chfr in DNA damage-induced ubiquitination.
  • To elucidate their impact on ATM kinase activation and genomic stability.

Main Methods:

  • Analysis of RNF8 and Chfr knockout (DKO) cells and mice.
  • Assessment of ATM kinase activation and DNA damage response pathways.
  • Investigation of histone ubiquitination and acetylation dynamics.

Main Results:

  • DKO cells exhibit suppressed ATM activation and hypersensitivity to ionizing radiation.
  • DKO mice develop thymic lymphomas with chromosome translocations.
  • RNF8 and Chfr synergistically regulate histone H4 Lys16 acetylation via MRG15-dependent complexes.

Conclusions:

  • RNF8 and Chfr act synergistically to modulate chromatin relaxation and ATM activation.
  • These chromatin-remodeling factors are essential for maintaining genomic stability in vivo.

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