Journal article
RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation
Cell Cycle, Vol.13(20), pp.3222-3231
10/15/2014
DOI: 10.4161/15384101.2014.950886
PMCID: PMC4615144
PMID: 25485502
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-ΔRFTS 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.
Details
- Title: Subtitle
- RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation
- Creators
- Bo-Kuan Wu - Department of Biochemistry; Carver College of Medicine; University of IowaSzu-Chieh Mei - Department of Biochemistry; Carver College of Medicine; University of IowaCharles Brenner - Department of Biochemistry; Carver College of Medicine; University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell Cycle, Vol.13(20), pp.3222-3231
- DOI
- 10.4161/15384101.2014.950886
- PMID
- 25485502
- PMCID
- PMC4615144
- NLM abbreviation
- Cell Cycle
- ISSN
- 1538-4101
- eISSN
- 1551-4005
- Publisher
- Taylor & Francis
- Language
- English
- Date published
- 10/15/2014
- Academic Unit
- Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9983788597202771
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