title: Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation.
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.
authors: The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.
authors: Yanzhong
authors: Y
authors: Yang
authors: The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.
authors: Kevin M
authors: KM
authors: McBride
authors: The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.
authors: Sean
authors: S
authors: Hensley
authors: The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.
authors: Yue
authors: Y
authors: Lu
authors: Department of Molecular & Cellular Biology, The University of California at Davis, Davis, CA 95616, USA.
authors: Frederic
authors: F
authors: Chedin
authors: The University of Texas MD Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA. Electronic address: mtbedford@mdanderson.org.
authors: Mark T
authors: MT
authors: Bedford
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D005786:Gene Expression Regulation; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C489427:MYC protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C532746:Tdrd3 protein, human; C588211:tdrd3 protein, mouse; D001120:Arginine; D004264:DNA Topoisomerases, Type I