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Updated: May 29, 2026
Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
Published on: September 28, 2012
p73 protein regulates DNA damage repair
Elena Zaika1, Jinxiong Wei, Dengping Yin
1Department of Surgery, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Ave., Nashville, TN 37232, USA.
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.
Insights
p73 protein is crucial for DNA repair during acid-induced damage in the esophagus, unlike p53 and p63. This finding highlights p73
Area of Science:
- Molecular Biology
- Oncology
- Gastroenterology
Background:
- The p53 tumor suppressor is well-studied, but the roles of p73 and p63 are less understood.
- Gastric reflux in the esophagus can lead to pathological conditions involving bile acids and acidic environments.
- These conditions are linked to the progression of esophageal adenocarcinoma.
Purpose of the Study:
- To investigate the role of p73 in the DNA damage response under pathological conditions caused by bile acids.
- To identify specific DNA repair mechanisms regulated by p73 in response to acid and bile acid exposure.
Main Methods:
- Exposure of normal cells to bile acids in acidic conditions.
- Analysis of p53 family protein activation (p73, p53, p63) and c-Abl kinase dependency.
- Utilizing a human DNA repair PCR array to identify affected genes.
- Investigating base excision repair glycosylases (SMUG1, MUTYH).
- Employing mouse models and cell cultures to assess DNA damage in p73-deficient conditions.
Main Results:
- p73 protein is selectively activated in response to bile acid and acid exposure, while p53 and p63 are not.
- Activated p73 induces DNA damage repair, regulating multiple DNA repair genes.
- SMUG1 and MUTYH glycosylases are transcriptionally regulated by p73.
- p73 deficiency leads to increased DNA damage in a mouse model.
Conclusions:
- p73 plays a predominant role in the DNA damage response to bile acid and acid exposure in esophageal conditions.
- p73 regulates key DNA repair pathways, including base excision repair.
- These findings reveal a critical function for p73 in protecting against DNA damage relevant to esophageal adenocarcinoma development.
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