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

TY - JOUR

T1 - THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate

AU - Polenkowski, Mareike

AU - Allister, Aldrige Bernardus

AU - de Lara, Sebastian Burbano

AU - Pierce, Andrew

AU - Geary, Bethany

AU - Bounkari, Omar El

AU - Wiehlmann, Lutz

AU - Hoffmann, Andrea

AU - Whetton, Anthony D.

AU - Tamura, Teruko

AU - Tran, Doan Duy Hai

N1 - © 2022 The Authors.

PY - 2023/1/20

Y1 - 2023/1/20

N2 - 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.

AB - 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.

U2 - 10.1016/j.isci.2022.105784

DO - 10.1016/j.isci.2022.105784

M3 - Article

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 1

M1 - 105784

ER -