p63 and p73 transcriptionally regulate genes involved in DNA repair.
The p53 family activates many of the same genes in response to DNA damage. Because p63 and p73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique transcriptional network. Therefore, we performed a genome-wide analysis using cells lacking the p53 family members after treatment with DNA damage. We identified over 100 genes involved in multiple pathways that were uniquely regulated by p63 or p73, and not p53. Further validation indicated that BRCA2, Rad51, and mre11 are direct transcriptional targets of p63 and p73. Additionally, cells deficient for p63 and p73 are impaired in DNA repair and p63+/-;p73+/- mice develop mammary tumors suggesting a novel mechanism whereby p63 and p73 suppress tumorigenesis.
Lin
Yu-Li
YL
Department of Molecular and Cellular Oncology, Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Sengupta
Shomit
S
Gurdziel
Katherine
K
Bell
George W
GW
Jacks
Tyler
T
Flores
Elsa R
ER
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D000076228:MRE11 Homologue Protein; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes