Arginine Methylation Facilitates the Recruitment of TOP3B to Chromatin to Prevent R Loop Accumulation

Yanzhong Yang, Kevin M. McBride, Sean Hensley, Yue Lu, Frederic Chedin, Mark T. Bedford

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Tudor domain-containing protein 3 (TDRD3) is a major methylarginine effector molecule that reads methyl-histone marks and facilitates gene transcription. However, the underlying mechanism by which TDRD3 functions as a transcriptional coactivator is unknown. We identified topoisomerase IIIB (TOP3B) as a component of the TDRD3 complex. TDRD3 serves as a molecular bridge between TOP3B and arginine-methylated histones. The TDRD3-TOP3B complex is recruited to the c-MYC gene promoter primarily by the H4R3me2a mark, and the complex promotes c-MYC gene expression. TOP3B relaxes negative supercoiled DNA and reduces transcription-generated R loops invitro. TDRD3 knockdown in cells increases R loop formation at the c-MYC locus, and Tdrd3 null mice exhibit elevated R loop formation at this locus in B cells. Tdrd3 null mice show significantly increased c-Myc/Igh translocation, a process driven by R loop structures. By reducing negative supercoiling and resolving R loops, TOP3B promotes transcription, protects against DNA damage, and reduces the frequency of chromosomal translocations.

Original languageEnglish (US)
Pages (from-to)484-497
Number of pages14
JournalMolecular Cell
Volume53
Issue number3
DOIs
StatePublished - Feb 6 2014

Fingerprint

Methylation
Chromatin
Arginine
Proteins
Histone Code
Superhelical DNA
Genetic Translocation
Histones
Genes
DNA Damage
Tudor Domain
B-Lymphocytes
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Arginine Methylation Facilitates the Recruitment of TOP3B to Chromatin to Prevent R Loop Accumulation. / Yang, Yanzhong; McBride, Kevin M.; Hensley, Sean; Lu, Yue; Chedin, Frederic; Bedford, Mark T.

In: Molecular Cell, Vol. 53, No. 3, 06.02.2014, p. 484-497.

Research output: Contribution to journalArticle

Yang, Yanzhong ; McBride, Kevin M. ; Hensley, Sean ; Lu, Yue ; Chedin, Frederic ; Bedford, Mark T. / Arginine Methylation Facilitates the Recruitment of TOP3B to Chromatin to Prevent R Loop Accumulation. In: Molecular Cell. 2014 ; Vol. 53, No. 3. pp. 484-497.
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