TY - JOUR

T1 - Translin facilitates RNA polymerase II dissociation and suppresses genome instability during RNase H2- and Dicer-deficiency

AU - Gomez Escobar, Natalia

AU - Alsaiari, Ahad

AU - Alahmadi, Hanadi Ahmed S

AU - Alzahrani, Othman

AU - Vernon, Ellen

AU - Althagafi, Hussam

AU - Almobadel, Nasser

AU - Pryce, David

AU - Wakeman, Jane

AU - Mcfarlane, Ramsay

N1 - RJM was funded by Cancer Research Wales (CRW did not designated a reference number; https://cancerresearchwales.co.uk/). A.A.A.A., H.A.S.A., O.A., H.A.E.A., and N.S.A. were all funded by individual studentship awards from the Government of the Kingdome of Saudi Arabia

PY - 2022/6/17

Y1 - 2022/6/17

N2 - The conserved nucleic acid binding protein Translin contributes to numerous facets of mammalian biology and genetic diseases. It was first identified as a binder of cancer-associated chromosomal translocation breakpoint junctions leading to the suggestion that it was involved in genetic recombination. With a paralogous partner protein, Trax, Translin has subsequently been found to form a hetero-octomeric RNase complex that drives some of its functions, including passenger strand removal in RNA interference (RNAi). The Translin-Trax complex also degrades the precursors to tumour suppressing microRNAs in cancers deficient for the RNase III Dicer. This oncogenic activity has resulted in the Translin-Trax complex being explored as a therapeutic target. Additionally, Translin and Trax have been implicated in a wider range of biological functions ranging from sleep regulation to telomere transcript control. Here we reveal a Trax- and RNAi-independent function for Translin in dissociating RNA polymerase II from its genomic template, with loss of Translin function resulting in increased transcription-associated recombination and elevated genome instability. This provides genetic insight into the longstanding question of how Translin might influence chromosomal rearrangements in human genetic diseases and provides important functional understanding of an oncological therapeutic target.

AB - The conserved nucleic acid binding protein Translin contributes to numerous facets of mammalian biology and genetic diseases. It was first identified as a binder of cancer-associated chromosomal translocation breakpoint junctions leading to the suggestion that it was involved in genetic recombination. With a paralogous partner protein, Trax, Translin has subsequently been found to form a hetero-octomeric RNase complex that drives some of its functions, including passenger strand removal in RNA interference (RNAi). The Translin-Trax complex also degrades the precursors to tumour suppressing microRNAs in cancers deficient for the RNase III Dicer. This oncogenic activity has resulted in the Translin-Trax complex being explored as a therapeutic target. Additionally, Translin and Trax have been implicated in a wider range of biological functions ranging from sleep regulation to telomere transcript control. Here we reveal a Trax- and RNAi-independent function for Translin in dissociating RNA polymerase II from its genomic template, with loss of Translin function resulting in increased transcription-associated recombination and elevated genome instability. This provides genetic insight into the longstanding question of how Translin might influence chromosomal rearrangements in human genetic diseases and provides important functional understanding of an oncological therapeutic target.

U2 - 10.1371/journal.pgen.1010267

DO - 10.1371/journal.pgen.1010267

M3 - Article

C2 - 35714159

VL - 18

JO - PLOS Genetics

JF - PLOS Genetics

SN - 1553-7390

IS - 6

M1 - e1010267

ER -