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

LSH, a protein related to SNF2 family of chromatin remodelling ATPases, is essential for correct establishment of DNA methylation levels and patterns in plants and mammalian cells. However, some of the phenotypes resulting from LSH deficiency cannot be easily explained 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 the wild-type cells. A more detailed characterization 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 compromised phosphorylation of checkpoint kinase CHK2. Furthermore, we demonstrate that the ability of LSH to hydrolyze 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 maintenance of genome stability in mammalian somatic cells, which is independent of its function in de novo DNA methylation during development.