It has been estimated that approximately 20% of the global cancer burden arises from individuals suffering chronic inflammatory responses. Such chronic inflammation is becoming accepted as an important contributor to the etiology of many different types of cancer. During chronic inflammation, macrophages, neutrophils, and other phagocytic cells generate reactive oxygen and nitrogen species (RONS) as normal antimicrobial agents to assist in eliminating infection and a major part of our proposed research will focus on the role that RONS play in tumorigenesis. RONS are known to induce damaged DNA bases, either directly via oxidation, deamination and indirectly via alkylation damage. We will explore how the repair of such damaged DNA bases influences the carcinogenic response by examining mice deficient in one (or more) of numerous DNA repair proteins (Aag, Abh2, Abh3, Myh, Ogg1, and Mbd4). We will examine these mutant animals under established mouse models of chronic inflammation-mediated carcinogenesis: AOM+DSS treatment, IL10 null mice, Mdr2 null mice, or the I:B-1-SR transgenic mice. These models of inflammation were chosen to examine the generality of the role of DNA repair in inflammation-mediated carcinogenesis by examining the contribution of DNA repair to tumors that arise via different mechanisms and in different tissues.
The Specific Aims of the proposed research fall under the following three headings: (I) explore the role of Aag in suppressing carcinogenesis associated with chronic inflammation;(II) explore the role of other DNA repair molecules/pathways in the protection against chronic inflammation-induced carcinogenesis;and (III) examine the molecular consequences behind increased carcinogenesis in DNA repair deficient animals. These studies will provide essential contributions to our understanding of the role of DNA repair in chronic inflammation- mediated carcinogenesis. Further, it will provide additional insight into our natural defenses against the toxic and carcinogenic effects of both environmental and endogenous DNA damaging agents.

Public Health Relevance

The contribution of chronic inflammation to carcinogenesis in humans (and mice) has been well- established. However, less is known about the putative role of DNA repair in inflammation-induced carcinogenesis, and we propose to investigate the contribution of DNA repair to carcinogenesis. Understanding how DNA repair contributes to carcinogenesis will provide insights into the mechanism by which chronic inflammation increases the chance of cancer as well as identify possible approaches to decrease cancer risk.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Okano, Paul
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Massachusetts Institute of Technology
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United States
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Chaim, Isaac A; Nagel, Zachary D; Jordan, Jennifer J et al. (2017) In vivo measurements of interindividual differences in DNA glycosylases and APE1 activities. Proc Natl Acad Sci U S A 114:E10379-E10388
Calvo, Jennifer A; Allocca, Mariacarmela; Fake, Kimberly R et al. (2016) Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner. Oncotarget 7:44950-44965
Meira, Lisiane B; Calvo, Jennifer A; Shah, Dharini et al. (2014) Repair of endogenous DNA base lesions modulate lifespan in mice. DNA Repair (Amst) 21:78-86
Ebrahimkhani, Mohammad R; Daneshmand, Ali; Mazumder, Aprotim et al. (2014) Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney. Proc Natl Acad Sci U S A 111:E4878-86
Calvo, Jennifer A; Moroski-Erkul, Catherine A; Lake, Annabelle et al. (2013) Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1. PLoS Genet 9:e1003413
Calvo, Jennifer A; Meira, Lisiane B; Lee, Chun-Yue I et al. (2012) DNA repair is indispensable for survival after acute inflammation. J Clin Invest 122:2680-9
Fu, Dragony; Calvo, Jennifer A; Samson, Leona D (2012) Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 12:104-20