RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

Bo Kuan Wu, Szu Chieh Mei, Charles Brenner

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, the molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in a gain of DNMT1 function. However, a substantial body of data suggested that RFTS is required for DNMT1 activity. Here, we demonstrate that deletion of RFTS alters DNMT1-dependent DNA methylation during malignant transformation. Compared to full-length DNMT1, ectopic expression of hyperactive DNMT1-DRFTS caused greater malignant transformation and enhanced promoter methylation with condensed chromatin structure that silenced DAPK and DUOX1 expression. Simultaneously, deletion of RFTS impaired DNMT1 chromatin association with pericentromeric Satellite 2 (SAT2) repeat sequences and produced DNA demethylation at SAT2 repeats and globally. To our knowledge, RFTS-deleted DNMT1 is the first single factor that can reprogram focal hypermethylation and global hypomethylation in parallel during malignant transformation. Our evidence suggests that the RFTS domain of DNMT1 is a target responsible for epigenetic changes in cancer.

Original languageEnglish (US)
Pages (from-to)3222-3231
Number of pages10
JournalCell Cycle
Volume13
Issue number20
DOIs
StatePublished - Oct 15 2014
Externally publishedYes

Keywords

  • Chromatin
  • DNA methylation
  • DNMT1
  • RFTS domain
  • Tumorigenicity

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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