Homeostatic regulation of base excision repair by a p53-induced phosphatase: linking stress response pathways with DNA repair proteins.
The p53 protein plays a central role in the integration of cellular stress responses. If the cell incurs DNA damage, p53-induced cell cycle arrest is accompanied by p53-facilitated DNA repair. In particular, p53 has been demonstrated to promote both nucleotide excision repair (NER) and base excision repair (BER). Once these repair processes are completed, p53 activity declines and the cell can reenter the cell cycle. A critical mediator of this p53 negative regulatory feedback loop is Mdm2, a p53 transcriptional target whose protein mediates p53 proteolytic degradation. Another such p53 transcriptional target that may function in a p53 negative regulation is the PPM1D phosphatase. PPM1D may inhibit p53 activity through inactivating dephosphorylation of the p38 MAP kinase. We have recently shown that PPM1D suppresses BER in part through dephosphorylation of a key BER effector, the nuclear isoform of uracil DNA glycosylase, or UNG2. This finding further links p53 signaling to DNA repair pathways and illustrates a mechanism by which activated DNA repair systems are returned to a deactivated, homeostatic state.
Lu
Xiongbin
X
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nguyen
Thuy-Ai
TA
Appella
Ettore
E
Donehower
Lawrence A
LA
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004247:DNA; D051736:Proto-Oncogene Proteins c-mdm2; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D051981:Uracil-DNA Glycosidase