title: Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo.
abstract: Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Singapore-MIT Alliance for Research and Technology, Singapore.
authors: Orsolya
authors: O
authors: Kiraly
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Guanyu
authors: G
authors: Gong
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Werner
authors: W
authors: Olipitz
authors: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Sureshkumar
authors: S
authors: Muthupalani
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Singapore-MIT Alliance for Research and Technology, Singapore.
authors: Bevin P
authors: BP
authors: Engelward
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D006657:Histones / Q000235:genetics; D059765:Homologous Recombination; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010179:Pancreas / Q000473:pathology; D012307:Risk Factors
chemical_list: D006657:Histones; C475961:gamma-H2AX protein, mouse
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