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Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):E4571-80. doi: 10.1073/pnas.1507709112. Epub 2015 Aug 4.

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer.

Author information

  • 1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; Department Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;
  • 2Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
  • 3Department Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;
  • 4Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; Department Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; jessig@mit.edu.

Abstract

During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.

KEYWORDS:

5-chloro-deoxycytidine; carcinogenesis; hypochlorite; inflammatory bowel disease; myeloperoxidase

PMID:
26243878
PMCID:
PMC4547254
DOI:
10.1073/pnas.1507709112
[PubMed - indexed for MEDLINE]
Free PMC Article
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