title: p73 protein regulates DNA damage repair.
abstract: Although the p53 tumor suppressor is relatively well characterized, much less is known about the functions of other members of the p53 family, p73 and p63. Here, we present evidence that in specific pathological conditions caused by exposure of normal cells to bile acids in acidic conditions, p73 protein plays the predominant role in the DNA damage response. These pathological conditions frequently occur during gastric reflux in the human esophagus and are associated with progression to esophageal adenocarcinoma. We found that despite strong DNA damage induced by bile acid exposure, only p73 (but not p53 and p63) is selectively activated in a c-Abl kinase-dependent manner. The activated p73 protein induces DNA damage repair. Using a human DNA repair PCR array, we identified multiple DNA repair genes affected by p73. Two glycosylases involved in base excision repair, SMUG1 and MUTYH, were characterized and found to be transcriptionally regulated by p73 in DNA damage conditions. Using a surgical procedure in mice, which recapitulates bile acid exposure, we found that p73 deficiency is associated with increased DNA damage. These findings were further investigated with organotypic and traditional cell cultures. Collectively our studies demonstrate that p73 plays an important role in the regulation of DNA damage repair.
authors: Department of Surgery, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Ave., Nashville, TN 37232, USA.
authors: Elena
authors: E
authors: Zaika
authors: Jinxiong
authors: J
authors: Wei
authors: Dengping
authors: D
authors: Yin
authors: Claudia
authors: C
authors: Andl
authors: Ute
authors: U
authors: Moll
authors: Wael
authors: W
authors: El-Rifai
authors: Alexander I
authors: AI
authors: Zaika
mesh_terms: D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000633:toxicity; D002478:Cells, Cultured; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000209:etiology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D045647:DNA Glycosylases; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase; C061738:mutY adenine glycosylase