Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Research Watch

GADD45A Recruits Demethylation Proteins to CpG Island Promoters

DOI: 10.1158/2159-8290.CD-RW2019-009 Published March 2019
  • Article
  • Info & Metrics
  • PDF
Loading
  • Major finding: GADD45A binding to R-loops promotes TET1 recruitment and DNA demethylation at CpG island promoters.

  • Concept: R-loop formation, DNA demethylation, and transcription occur sequentially during the cell cycle.

  • Impact: GADD45A is an epigenetic reader of R-loops formed by antisense lncRNAs at promoter CpG islands.

Previous studies have shown that the antisense long noncoding RNA (lncRNA) TCF21 antisense RNA inducing promoter demethylation (TARID) activates transcription of the tumor suppressor gene TCF21 by recruiting growth arrest and DNA damage inducible A (GADD45A) and stimulating TET1-mediated DNA demethylation. Building on these findings, Arab and colleagues found that the lncRNA TARID formed a DNA–RNA hybrid R-loop at the CpG island promoter of TCF21. The R-loop–forming sequence overlapped with a region of DNA demethylation in the TCF21 promoter, and degradation of this R-loop by RNase H1 decreased TCF21 expression, suggesting that TARID-dependent R-loop formation directs promoter demethylation and is necessary for TCF21 transcriptional activation. GADD45A, a stress response protein implicated in repair-mediated DNA demethylation, directly interacted with the TARID–TCF21 R-loop and with DNA–RNA hybrid structures in vitro and recruited the TET1 demethylase in an R-loop–dependent manner. Transcription of TARID and TCF21 were temporally regulated during the cell cycle, as TARID transcription occurred in early- to mid-S phase and was followed by accumulation of R-loops at the TCF21 promoter, GADD45A binding to R-loops, and TCF21 demethylation and transcriptional activation. Consistent with a role for R-loops as sites of promoter demethylation, global levels of oxidized 5′methylcytosine derivatives were enriched at R-loops. Chromatin immunoprecipitation sequencing of mouse embryonic stem cells revealed that TET1 was associated with thousands of genomic R-loops, in particular those found in CpG island regions around transcription start sites and a subset of regions associated with antisense lncRNAs. TET1 binding to R-loops was also detected at the promoters of orthologous genes in human primary skin fibroblasts, and knockdown of GADD45A and GADD45B specifically reduced TET1 recruitment to these R-loop–containing promoters. These findings identify GADD45A as an epigenetic reader of promoter-associated R-loops that targets demethylation factors to CpG island promoters to regulate transcription.

Arab K, Karaulanov E, Musheev M, Trnka P, Schäfer A, Grummt I, et al. GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat Genet 2019;51:217–23.

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 9 (3)
March 2019
Volume 9, Issue 3
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
GADD45A Recruits Demethylation Proteins to CpG Island Promoters
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
GADD45A Recruits Demethylation Proteins to CpG Island Promoters
Cancer Discov March 1 2019 (9) (3) 315; DOI: 10.1158/2159-8290.CD-RW2019-009

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
GADD45A Recruits Demethylation Proteins to CpG Island Promoters
Cancer Discov March 1 2019 (9) (3) 315; DOI: 10.1158/2159-8290.CD-RW2019-009
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Notes
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

Research Watch

  • In Vivo CRISPR Screen Identifies FLI1 as Regulator of Effector T Cells
  • Trial Supports Combination Treatment and New Target for Multiple Myeloma
  • Mitochondrial DNA Damage Triggers an IFN-Mediated Immune Response
Show more Research Watch

Epigenetics

  • Computational Tool Characterizes Previously Unidentified Tumor Subtypes
  • FBXO44 Silences Repetitive Elements during DNA Replication in Cancer
  • H1 Loss Increases Accessibility of Stemness Genes to Drive Lymphoma
Show more Epigenetics
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement