Abstract
The tumor suppressor gene phosphatase and tensin homolog deleted on chromosome 10 gene (PTEN) encodes a 403-aminao acid protein with an evolutionarily conserved dual lipid and protein phosphatase domain at the NH2 terminus. Germ line mutations in PTEN confer elevated risks in the development of many cancers. PTEN is well documented in antagonizing the phosphoinosital-3-kinase (PI3K)/AKT signaling in the cytoplasm. Here, we reveal novel functions for PTEN in the DNA-damage response. We show phosphorylated PTEN-Ser380 recruitments to nuclear in a sprinkle manner and colocations with ATM-pSer-1981 and γ-H2AX at the DNA damage sites. Using large-scale chromatin relaxation mammalian cell model, we find PTEN induces large-scale chromatin decondensation, the protein phosphatase activity and phosphorylation statue of the PTEN-Ser380 are essential for chromatin unfolding. In addition, the lipid and protein phosphatase domain significantly increases the extent of chromatin unfolding as compared with wild type PTEN. Inhibition of ATM significantly down-regulates the phosphorylation level of PTEN and impairs the chromatin remodeling activity. Our results, showing that PTEN couples to DNA damage response in chromatin remodeling way, have important implications for better understanding of PTEN’s tumor-suppressor function and also reveal the potential target for drug design.
