Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage

Ning Ding, Emily M. Bonham, Brooke E. Hannon, Thomas R. Amick, Stephen B. Baylin, Heather O'Hagan

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein-protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.

Original languageEnglish (US)
Pages (from-to)244-254
Number of pages11
JournalJournal of Molecular Cell Biology
Volume8
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

DNA Mismatch Repair
Methyltransferases
DNA Damage
DNA
Epigenomics
CpG Islands
Proteins
Inflammation
GC Rich Sequence
DNA Methylation
DNA Repair
Colonic Neoplasms
Hydrogen Peroxide
Chromatin
Reactive Oxygen Species
Neoplasms
Epithelial Cells
Genome
Genes

Keywords

  • DNA repair
  • DNMT1
  • epigenetics
  • mismatch repair
  • oxidative damage
  • SIRT1
  • transcription

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. / Ding, Ning; Bonham, Emily M.; Hannon, Brooke E.; Amick, Thomas R.; Baylin, Stephen B.; O'Hagan, Heather.

In: Journal of Molecular Cell Biology, Vol. 8, No. 3, 01.06.2016, p. 244-254.

Research output: Contribution to journalArticle

Ding, Ning ; Bonham, Emily M. ; Hannon, Brooke E. ; Amick, Thomas R. ; Baylin, Stephen B. ; O'Hagan, Heather. / Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. In: Journal of Molecular Cell Biology. 2016 ; Vol. 8, No. 3. pp. 244-254.
@article{67736525c1cf48a4b3563b9005d5c74c,
title = "Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage",
abstract = "At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein-protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.",
keywords = "DNA repair, DNMT1, epigenetics, mismatch repair, oxidative damage, SIRT1, transcription",
author = "Ning Ding and Bonham, {Emily M.} and Hannon, {Brooke E.} and Amick, {Thomas R.} and Baylin, {Stephen B.} and Heather O'Hagan",
year = "2016",
month = "6",
day = "1",
doi = "10.1093/jmcb/mjv050",
language = "English (US)",
volume = "8",
pages = "244--254",
journal = "Journal of Molecular Cell Biology",
issn = "1674-2788",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage

AU - Ding, Ning

AU - Bonham, Emily M.

AU - Hannon, Brooke E.

AU - Amick, Thomas R.

AU - Baylin, Stephen B.

AU - O'Hagan, Heather

PY - 2016/6/1

Y1 - 2016/6/1

N2 - At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein-protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.

AB - At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein-protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.

KW - DNA repair

KW - DNMT1

KW - epigenetics

KW - mismatch repair

KW - oxidative damage

KW - SIRT1

KW - transcription

UR - http://www.scopus.com/inward/record.url?scp=84978871086&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978871086&partnerID=8YFLogxK

U2 - 10.1093/jmcb/mjv050

DO - 10.1093/jmcb/mjv050

M3 - Article

C2 - 26186941

AN - SCOPUS:84978871086

VL - 8

SP - 244

EP - 254

JO - Journal of Molecular Cell Biology

JF - Journal of Molecular Cell Biology

SN - 1674-2788

IS - 3

ER -