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

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

Author information

1
The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.
2
Department of Molecular & Cellular Biology, The University of California at Davis, Davis, CA 95616, USA.
3
The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA. Electronic address: mtbedford@mdanderson.org.

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 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.

PMID:
24507716
PMCID:
PMC3959860
DOI:
10.1016/j.molcel.2014.01.011
[Indexed for MEDLINE]
Free PMC Article
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