THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate
Mareike Polenkowski,
Aldrige Bernardus Allister,
Sebastian Burbano de Lara,
Andrew Pierce,
Bethany Geary,
Omar El Bounkari,
Lutz Wiehlmann,
Andrea Hoffmann,
Anthony D. Whetton,
Teruko Tamura,
Doan Duy Hai Tran
Affiliations
Mareike Polenkowski
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover D-30623, Germany; Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover D-30623, Germany
Aldrige Bernardus Allister
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover D-30623, Germany; Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover D-30623, Germany
Sebastian Burbano de Lara
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Andrew Pierce
Stem Cell and Leukemia Protoemics Laboratory, University of Manchester, Manchester M20 3LJ, UK
Bethany Geary
Stem Cell and Leukemia Protoemics Laboratory, University of Manchester, Manchester M20 3LJ, UK
Omar El Bounkari
Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität, 81377 Munich, Germany
Lutz Wiehlmann
Pädiatrische Pneumologie Hannover Medical School, Hannover D-30623, Germany
Andrea Hoffmann
Department of Orthopedic Surgery, Hannover Medical School, Hannover D-30623, Germany
Anthony D. Whetton
Stoller Biomarker Discovery Centre, University of Manchester, Manchester M13 9PL, UK
Teruko Tamura
Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover D-30623, Germany
Doan Duy Hai Tran
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover D-30623, Germany; Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover D-30623, Germany; Corresponding author
Summary: THOC5, a member of the THO complex, is essential for the 3′processing of some inducible genes, the export of a subset of mRNAs and stem cell survival. Here we show that THOC5 depletion results in altered 3′cleavage of >50% of mRNAs and changes in RNA polymerase II binding across genes. THOC5 is recruited close to high-density polymerase II sites, suggesting that THOC5 is involved in transcriptional elongation. Indeed, measurement of elongation rates in vivo demonstrated decreased rates in THOC5-depleted cells. Furthermore, THOC5 is preferentially recruited to its target genes in slow polymerase II cells compared with fast polymerase II cells. Importantly chromatin-associated THOC5 interacts with CDK12 (a modulator of transcription elongation) and RNA helicases DDX5, DDX17, and THOC6 only in slow polymerase II cells. The CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. These data demonstrate a novel function of THOC5 in transcription elongation.
