The SNF2 family ATPase LSH promotes phosphorylation of H2AX and efficient repair of DNA double-strand breaks in mammalian cells

Joe Burrage, Ausma Termanis, Andreas Geissner, Kevin Myant, Katrina Gordon, Irina Stancheva

Research output: Contribution to journalArticlepeer-review

Abstract

LSH, a protein related to the SNF2 family of chromatin-remodelling ATPases, is essential for the correct establishment of DNA methylation levels and patterns in plants and mammalian cells. However, some of the phenotypes resulting from LSH deficiency cannot be explained easily by defects in DNA methylation. Here we show that LSH-deficient mouse and human fibroblasts show reduced viability after exposure to ionizing radiation and repair DNA double-strand breaks less efficiently than wild-type cells. A more detailed characterisation of this phenotype revealed that, in the absence of LSH, the histone variant H2AX is not efficiently phosphorylated in response to DNA damage. This results in impaired recruitment of MDC1 and 53BP1 proteins to DNA double-strand breaks and compromises phosphorylation of checkpoint kinase CHK2. Furthermore, we demonstrate that the ability of LSH to hydrolyse ATP is necessary for efficient phosphorylation of H2AX at DNA double-strand breaks and successful repair of DNA damage. Taken together, our data reveal a previously unsuspected role of LSH ATPase in the maintenance of genome stability in mammalian somatic cells, which is independent of its function in de novo DNA methylation during development.
Original languageEnglish
Pages (from-to)5524-5534
Number of pages11
JournalJournal of Cell Science
Volume125
Issue number22
Early online date3 Sep 2012
DOIs
Publication statusPublished - 15 Nov 2012

Keywords

  • Adenosine Triphosphatases
  • Animals
  • Checkpoint Kinase 2
  • DNA Breaks, Double-Stranded
  • DNA Helicases
  • DNA Methylation
  • DNA Repair
  • Enzyme Activation
  • Fibroblasts
  • Histones
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Mammals
  • Mice
  • Mutant Proteins
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Radiation, Ionizing
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction
  • Transcription Factors
  • DNA damage
  • LSH
  • Chromatin
  • Chromatin remodelling

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