Document Detail


PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response.
MedLine Citation:
PMID:  22797300     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The DNA damage response (DDR) is a complex regulatory network that is critical for maintaining genome integrity. Posttranslational modifications are widely used to ensure strict spatiotemporal control of signal flow, but how the DDR responds to environmental cues, such as changes in ambient oxygen tension, remains poorly understood. We found that an essential component of the ATR/CHK1 signaling pathway, the human homolog of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2), associated with and was hydroxylated by prolyl hydroxylase domain protein 3 (PHD3). HCLK2 hydroxylation was necessary for its interaction with ATR and the subsequent activation of ATR/CHK1/p53. Inhibiting PHD3, either with the pan-hydroxylase inhibitor dimethyloxaloylglycine (DMOG) or through hypoxia, prevented activation of the ATR/CHK1/p53 pathway and decreased apoptosis induced by DNA damage. Consistent with these observations, we found that mice lacking PHD3 were resistant to the effects of ionizing radiation and had decreased thymic apoptosis, a biomarker of genomic integrity. Our identification of HCLK2 as a substrate of PHD3 reveals the mechanism through which hypoxia inhibits the DDR, suggesting hydroxylation of HCLK2 is a potential therapeutic target for regulating the ATR/CHK1/p53 pathway.
Authors:
Liang Xie; Xinchun Pi; Ashutosh Mishra; Guohua Fong; Junmin Peng; Cam Patterson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-17
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-01     Completed Date:  2012-10-25     Revised Date:  2013-10-10    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2827-36     Citation Subset:  AIM; IM    
Affiliation:
UNC McAllister Heart Institute and Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. pxliang@email.unc.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Cell Cycle Proteins / metabolism
DNA Damage*
Dioxygenases / antagonists & inhibitors,  genetics,  metabolism*
Female
Gene Knockdown Techniques
HeLa Cells
Humans
Male
Mice
Mice, Knockout
Mice, Transgenic
Procollagen-Proline Dioxygenase / deficiency,  genetics,  metabolism*
Protein Kinases / metabolism
Protein-Serine-Threonine Kinases / metabolism*
Protein-Tyrosine Kinases / metabolism*
RNA, Small Interfering / genetics
Recombinant Proteins / genetics,  metabolism
Signal Transduction
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
P30 CA016086/CA/NCI NIH HHS; R01 GM61728/GM/NIGMS NIH HHS; R01 HL61656/HL/NHLBI NIH HHS; R37 65619//PHS HHS
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/RNA, Small Interfering; 0/Recombinant Proteins; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; EC 1.13.11.-/Dioxygenases; EC 1.14.11.2/EGLN3 protein, human; EC 1.14.11.2/PHD3 protein, mouse; EC 1.14.11.2/Procollagen-Proline Dioxygenase; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.1.-/Clk dual-specificity kinases; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

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