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dc.contributor.authorChang, Lufen
dc.contributor.authorZhou, Bingsen
dc.contributor.authorHu, Shuya
dc.contributor.authorGuo, Robin
dc.contributor.authorLiu, Xiyong
dc.contributor.authorJones, Stephen N.
dc.contributor.authorYen, Yun
dc.date2022-08-11T08:09:15.000
dc.date.accessioned2022-08-23T16:23:55Z
dc.date.available2022-08-23T16:23:55Z
dc.date.issued2008-11-19
dc.date.submitted2011-01-28
dc.identifier.citationProc Natl Acad Sci U S A. 2008 Nov 25;105(47):18519-24. Epub 2008 Nov 17. <a href="http://dx.doi.org/10.1073/pnas.0803313105">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.0803313105
dc.identifier.urihttp://hdl.handle.net/20.500.14038/36010
dc.description.abstractRibonucleotide 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=19015526&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.0803313105
dc.subjectCell Cycle Proteins
dc.subject*DNA Damage
dc.subjectDNA Repair
dc.subjectDNA-Binding Proteins
dc.subjectHumans
dc.subjectPhosphorylation
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectRibonucleotide Reductases
dc.subjectSerine
dc.subjectTumor Suppressor Proteins
dc.subjectUltraviolet Rays
dc.subjectCell Biology
dc.titleATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume105
dc.source.issue47
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/jones/14
dc.identifier.contextkey1750947
html.description.abstract<p>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.</p>
dc.identifier.submissionpathjones/14
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages18519-24


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