The THP1-SAC3-SUS1-CDC31 Complex Works in Transcription Elongation-mRNA Export Preventing RNA-mediated Genome Instability

TLDR

The THO/TREX complex and related mRNA export factors such as Thp1–Sac3 are known to maintain genome integrity, but the role of the SAGA‑associated component Sus1 in transcription and genome stability remains unclear. The study demonstrates that Thp1, Sac3, and Sus1 form a functional unit that promotes mRNP biogenesis and preserves genome integrity independently of SAGA. The data show that R‑loop formation in Thp1–Sac3–Sus1–Cdc31 contributes to genome instability, and that this complex, together with THO/TREX, establishes an RNA‑dependent pathway linking transcription elongation to mRNA export that safeguards genetic integrity.

Abstract

The eukaryotic THO/TREX complex, involved in mRNP biogenesis, plays a key role in the maintenance of genome integrity in yeast. mRNA export factors such as Thp1-Sac3 also affect genome integrity, but their mutations have other phenotypes different from those of THO/TREX. Sus1 is a novel component of SAGA transcription factor that also associates with Thp1-Sac3, but little is known about its effect on genome instability and transcription. Here we show that Thp1, Sac3, and Sus1 form a functional unit with a role in mRNP biogenesis and maintenance of genome integrity that is independent of SAGA. Importantly, the effects of ribozyme-containing transcription units, RNase H, and the action of human activation-induced cytidine deaminase on transcription and genome instability are consistent with the possibility that R-loops are formed in Thp1-Sac3-Sus1-Cdc31 as in THO mutants. Our data reveal that Thp1-Sac3-Sus1-Cdc31, together with THO/TREX, define a specific pathway connecting transcription elongation with export via an RNA-dependent dynamic process that provides a feedback mechanism for the control of transcription and the preservation of genetic integrity of transcribed DNA regions.