ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage
Department of Cell Biology
Cell Cycle Proteins; *DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-mdm2; Ribonucleotide Reductases; Serine; Tumor Suppressor Proteins; Ultraviolet Rays
Ribonucleotide reductase small subunit p53R2 was identified as a p53 target gene that provides dNTP for DNA damage repair. However, the slow transcriptional induction of p53R2 in RNA may not be rapid enough for prompt DNA damage repair, which has to occur within a few hours of damage. Here, we demonstrate that p53R2 becomes rapidly phosphorylated at Ser(72) by ataxia telangiectasia mutated (ATM) within 30 min after genotoxic stress. p53R2, as well as its heterodimeric partner RRM1, are associated with ATM in vivo. Mutational studies further indicate that ATM-mediated Ser(72) phosphorylation is essential for maintaining p53R2 protein stability and conferring resistance to DNA damage. The mutation of Ser(72) on p53R2 to alanine results in the hyperubiquitination of p53R2 and reduces p53R2 stability. MDM2, a ubiquitin ligase for p53, interacts and facilitates ubiquitination of the S72A-p53R2 mutant more efficiently than WT-p53R2 after DNA damage in vivo. Our results strongly suggest a novel mechanism for the regulation of p53R2 activity via ATM-mediated phosphorylation at Ser(72) and MDM2-dependent turnover of p53R2 dephosphorylated at the same residue.
DOI of Published Version
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18519-24. Epub 2008 Nov 17. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Chang, Lufen; Zhou, Bingsen; Hu, Shuya; Guo, Robin; Liu, Xiyong; Jones, Stephen N.; and Yen, Yun, "ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage" (2008). Stephen Jones Lab Publications. 14.