PARP inhibitors have been used in the clinical treatment for tumors with BRCA1 or BRCA2 mutations. The major function of PARP inhibitors is to suppress PARP1 and PARP2 mediated poly(ADP-ribosyl)ation, a unique posttranslational modification, mainly induced in DNA damage. Suppression of PARylation by PARP inhibitors abolishes early recruitment of DNA damage response factors and impairs DNA damage repair. Because PARylation is a very transient posttranslational modification, normal cells have other repair mechanism to compensate for the loss of PARylation-dependent DNA damage response. However, a set of tumor cells harbor genetic mutations, such as BRCA1/2 mutations, which have already led to impaired DSB repair. With additional PARP inhibitor treatment to abolish PARylation-dependent DNA damage response, these tumor cells will undergo apoptosis. Thus, PARP inhibitor treatment selectively kills tumor cells with DNA damage repair defects, such as BRCA tumors. However, recent clinical trials suggest that only a set of BRCA tumors respond effectively to the PARP inhibitor treatment. Moreover, accumulated evidence indicates that PARP inhibitor treatment is able to suppress the growth of other types of tumor besides BRCA tumors. Thus, to extend the therapeutic potential of PARP inhibitors in cancer treatment, we explored biomarkers for the PARP inhibitor treatment. Interestingly, we found that NADP+, an NAD+ derivative, can suppress the activity of PARPs both in vitro and in vivo. Thus, we hypothesize that NADP+ is an endogenous PARP inhibitor, and the high level of NADP+ in tumor cells is able to sensitize tumor cells for DNA damaging related cancer therapy, including chemotherapy and radiation therapy. In this application, we plan to examine 1) the role of NADP+ in poly(ADP-ribosyl)ation-dependent DNA damage repair; 2) the molecular mechanism that regulates the cellular level of NADP+; 3) the role of NADP+ in sensitizing tumor cells to DNA damaging-associated cancer therapy. Taken together, the proposed study will not only reveal novel molecular mechanism in DNA damage repair, but also identify novel therapeutic approach for cancer treatment.

Public Health Relevance

Although PARP inhibitors have been approved by FDA for the treatment of BRCA tumors, recent clinical studies suggest that not all the BRCA tumors respond well to PARP inhibitors, and other regulators may mediate cellular sensitivity to PARP inhibitors. In our preliminary studies, we found that NADP+ is a novel endogenous PARP inhibitor. In this proposal, we plan to examine the mechanism by which NADP+ participates in DNA damage repair, and if NADP+ can serve as a biomarker and a sensitizer for cancer therapy including chemotherapy and radiation therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA130899-11
Application #
9739132
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2009-05-01
Project End
2024-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Chen, Qian; Kassab, Muzaffer Ahmad; Dantzer, Fran├žoise et al. (2018) PARP2 mediates branched poly ADP-ribosylation in response to DNA damage. Nat Commun 9:3233
Wang, Jiaxu; Yuan, Zenglin; Cui, Yaqi et al. (2018) Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR. Nat Commun 9:2689
Wang, Mengxi; Yuan, Zenglin; Xie, Rong et al. (2018) Structure-function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation. J Biol Chem 293:14470-14480
Liu, Yidan; Zhang, Bin; Meng, Xiaoyu et al. (2017) UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures. Epigenetics 12:551-560
Li, Mo; Chen, Qian; Ma, Teng et al. (2017) Targeting reactive nitrogen species suppresses hereditary pancreatic cancer. Proc Natl Acad Sci U S A 114:7106-7111
Han, Deqiang; Chen, Qian; Shi, Jiazhong et al. (2017) CTCF participates in DNA damage response via poly(ADP-ribosyl)ation. Sci Rep 7:43530
Li, Mo; Chen, Qian; Yu, Xiaochun (2017) Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer. Cancer Res 77:448-458
Evans, Joseph R; Zhao, Shuang G; Chang, S Laura et al. (2016) Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer. JAMA Oncol 2:471-80
Yu, Xiaochun (2016) A special issue on the DNA damage response and genomic instability. Acta Biochim Biophys Sin (Shanghai) 48:593
Liu, Yidan; Zhang, Bin; Kuang, Henry et al. (2016) Zinc Finger Protein 618 Regulates the Function of UHRF2 (Ubiquitin-like with PHD and Ring Finger Domains 2) as a Specific 5-Hydroxymethylcytosine Reader. J Biol Chem 291:13679-88

Showing the most recent 10 out of 53 publications