JAK2 regulates mismatch repair protein-mediated epigenetic alterations in response to oxidative damage

Ning Ding, Sam A. Miller, Sudha S. Savant, Heather M. O'Hagan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H 2 O 2 ), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H 2 O 2 -induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H 2 O 2 -induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage-induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 60:308–319, 2019.

Original languageEnglish (US)
Pages (from-to)308-319
Number of pages12
JournalEnvironmental and Molecular Mutagenesis
Volume60
Issue number4
DOIs
StatePublished - May 2019

Keywords

  • DNMT1
  • EZH2
  • JAK2
  • MSH2
  • MSH6
  • oxidative damage

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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