Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation

Mol Cell. 2014 Feb 6;53(3):484-97. doi: 10.1016/j.molcel.2014.01.011.


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 in vitro. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / metabolism
  • Chromatin / metabolism*
  • DNA Topoisomerases, Type I / metabolism*
  • Gene Expression Regulation
  • Genomic Instability
  • HEK293 Cells
  • Humans
  • Methylation
  • Mice
  • Mice, Knockout
  • Protein Transport
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteins / physiology
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Transcription, Genetic


  • Chromatin
  • MYC protein, human
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Tdrd3 protein, human
  • tdrd3 protein, mouse
  • Arginine
  • DNA Topoisomerases, Type I