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

doi:10.1016/j.isci.2022.105784

THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate

iScience. 2022 Dec 9;26(1):105784. doi: 10.1016/j.isci.2022.105784. eCollection 2023 Jan 20.

Authors

Affiliations

¹ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover D-30623, Germany.
² Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover D-30623, Germany.
³ Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover D-30623, Germany.
⁴ German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ Stem Cell and Leukemia Protoemics Laboratory, University of Manchester, Manchester M20 3LJ, UK.
⁶ Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
⁷ Pädiatrische Pneumologie Hannover Medical School, Hannover D-30623, Germany.
⁸ Department of Orthopedic Surgery, Hannover Medical School, Hannover D-30623, Germany.
⁹ Stoller Biomarker Discovery Centre, University of Manchester, Manchester M13 9PL, UK.

Abstract

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.

Keywords: Cell biology; Molecular biology.