title: DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo.
abstract: Cancer susceptibility varies between people, affected by genotoxic exposures, genetic makeup and physiological state. Yet, how these factors interact among each other to define cancer risk is largely unknown. Here, we uncover the interactive effects of genetical, environmental and physiological factors on genome rearrangements driven by homologous recombination (HR). Using FYDR mice to quantify HR-driven rearrangements in pancreas tissue, we show that DNA methylation damage (induced by methylnitrosourea) and cell proliferation (induced by thyroid hormone) each induce HR and together act synergistically to induce HR-driven rearrangements in vivo. These results imply that developmental or regenerative proliferation as well as mitogenic exposures may sensitize tissues to DNA damaging exposures. We exploited mice genetically deficient in alkyl-adenine DNA glycosylase (Aag) to analyse the relative contributions of unrepaired DNA base lesions versus intermediates formed during base excision repair (BER). Remarkably, results show that, in the pancreas, Aag is a major driver of spontaneous HR, indicating that BER intermediates (including abasic sites and single strand breaks) are more recombinogenic than the spontaneous base lesions removed by Aag. Given that mammals have about a dozen DNA glycosylases, these results point to BER as a major source of pressure on the HR pathway in vivo. Taken together, methylation damage, cell proliferation and Aag interact to define the risk of HR-driven sequence rearrangements in vivo. These data identify important sources of sequence changes in a cancer-relevant organ, and advance the effort to identify populations at high-risk for cancer.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kiraly
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and.
authors.forename: Guanyu
authors.initials: G
authors.lastname: Gong
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and.
authors.forename: Megan D
authors.initials: MD
authors.lastname: Roytman
authors.affiliation: Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore bevin@mit.edu.
authors.forename: Bevin P
authors.initials: BP
authors.lastname: Engelward
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D059765:Homologous Recombination; D006801:Humans; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D008770:Methylnitrosourea; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C437225:adenine glycosylase