Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations

Elife. 2018 May 8;7:e32222. doi: 10.7554/eLife.32222.

Abstract

Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment. The etoposide-induced phosphorylation of ARP8 is regulated by ATM and ATR, and attenuates its interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of INO80 and RAD51 onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8, regulated by ATM, plays an important role in maintaining the fidelity of DNA repair to prevent the etoposide-induced 11q23 abnormalities.

Keywords: ARP8 phosphorylation; ATM; ATR; INO80; RAD51; chromosome translocations; chromosomes; gene expression; human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Line
  • DNA Helicases / metabolism*
  • DNA Repair
  • DNA-Binding Proteins
  • Etoposide / toxicity
  • Humans
  • Microfilament Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Rad51 Recombinase / metabolism
  • Translocation, Genetic*

Substances

  • ACTR8 protein, human
  • DNA-Binding Proteins
  • Microfilament Proteins
  • Etoposide
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • RAD51 protein, human
  • Rad51 Recombinase
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • INO80 protein, human

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.