The role of DNA polymerase eta in DNA damage response and p53 activation This application is proposed to address the signaling pathway of DNA polymerase eta (PolH) in DNA damage response and p53 activation and the effect of the signal pathway interaction between p53 and PolH on cell survival and death. In an effort to characterize the role of p53 in DNA damage response, we found that PolH can be induced by DNA damage in a p53-dependent manner. PolH is the product of the Xeroderma Pigmentosum (XP) gene. XP is an autosomal recessive disorder, and XP patients are prone to early onset of malignant skin cancers. Interestingly, we found that knockdown of PolH enhances cell survival by inhibiting DNA damage-induced apoptosis. We also found that DNA damage-induced activation of p53 is impaired in both PolH-knockdown and PolH-null cells, which can be rescued by a reconstituted PolH. Furthermore, we found that PolH modulates DNA damage response via the ATM- ChK2-p53 pathway. Finally, our recent preliminary studies showed that the stability of PolH protein is decreased upon DNA damage and PolH physically interacts with Mdm2 and Pirh2, both of which are a p53 target gene and an E3 ligase. Taken together, we hypothesize that PolH activity is regulated by multiple pathways and PolH has novel functions in DNA damage response and p53 activation. To further address this, the following three specific aims are proposed: (1) to determine whether and how PolH expression is regulated at basal and DNA damage conditions;(2) to determine the functional significance of the interaction between PolH and Mdm2 or Pirh2;and (3) to determine the role of PolH in DNA damage response and p53 activation.
It is well-known that loss of p53 tumor suppressor leads to genome instability and Xeroderma Pigmentosum (XP) patients often exhibit a high frequency of genome instability. In addition, the magnitude of genome instability is much higher in cells lacking both Xeroderma Pigmentosum (XP) and p53 genes than cells lacking either one individually. Interestingly, we found that PolH, the XPV gene product, is a novel p53 target gene and knockdown of PolH enhances cell survival by inhibiting DNA damage-induced apoptosis. Surprisingly, we found that activation of p53 following DNA damage is impaired in both PolH-knockdown and PolH-null cells, which can be rescued by reconstituted PolH. Given the fact that loss of PolH predisposes XP patients to early onset of multiple malignant skin cancers and that p53 is a tumor suppressor, further studies to address how PolH modulates p53 activation and DNA damage response are highly significant and warranted.
|Yan, Wensheng; Scoumanne, Ariane; Jung, Yong-Sam et al. (2016) Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation. Genes Dev 30:522-34|
|Ren, Cong; Zhang, Jin; Yan, Wensheng et al. (2016) RNA-binding Protein PCBP2 Regulates p73 Expression and p73-dependent Antioxidant Defense. J Biol Chem 291:9629-37|
|Zhang, Yanhong; Young, Ashley; Zhang, Jin et al. (2015) P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition. Oncotarget 6:13994-4004|
|Kol, Amir; Arzi, Boaz; Athanasiou, Kyriacos A et al. (2015) Companion animals: Translational scientist's new best friends. Sci Transl Med 7:308ps21|
|Zhang, Y; Yan, W; Chen, X (2014) P63 regulates tubular formation via epithelial-to-mesenchymal transition. Oncogene 33:1548-57|
|Ren, Cong; Cho, Seong-Jun; Jung, Yong-Sam et al. (2014) DNA polymerase Î· is regulated by poly(rC)-binding protein 1 via mRNA stability. Biochem J 464:377-86|
|Yan, Wensheng; Chen, Xiufang; Zhang, Yanhong et al. (2013) Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of Î”Np63 protein. J Biol Chem 288:2907-13|
|Berger, C; Qian, Y; Chen, X (2013) The p53-estrogen receptor loop in cancer. Curr Mol Med 13:1229-40|
|Jung, Yong-Sam; Qian, Yingjuan; Yan, Wensheng et al. (2013) Pirh2 E3 ubiquitin ligase modulates keratinocyte differentiation through p63. J Invest Dermatol 133:1178-87|
|Qian, Yingjuan; Chen, Xinbin (2013) Senescence regulation by the p53 protein family. Methods Mol Biol 965:37-61|
Showing the most recent 10 out of 24 publications