Article

The THP1-SAC3-SUS1-CDC31 complex works in transcription elongation-mRNA export preventing RNA-mediated genome instability

Centro Andaluz de Biologia Molecular y Medicina Regenerativa, Universidad de Sevilla-CSIC, 41092 Sevilla, Spain.
Molecular biology of the cell (Impact Factor: 4.47). 08/2008; 19(10):4310-8. DOI: 10.1091/mbc.E08-04-0355
Source: PubMed

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.

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    • "The N-terminal RRM, LRR, and NTF2L domains are thought to recognize RNA, whereas the NTF2L domain binds Mtr2 and, together with the UBA domain, provides lowaffinity binding sites for nucleoporin FG repeats (Kang et al., 1999; Liker et al., 2000; Fribourg et al., 2001; Bachi et al., 2000; Grant et al., 2002, 2003; Aibara et al., 2015). Transcription export complex 2 (TREX-2) contributes to both mRNA nuclear export and its integration with the nuclear steps of the gene expression pathway (Rodriguez-Navarro et al., 2004; Gonzá lez-Aguilera et al., 2008). TREX-2 is based on a Sac3 scaffold (Figure 1A) to which Thp1, Sem1, Sus1, and Cdc31 bind, and is localized primarily at NPCs through interactions with proteins located on the nucleoplasmic face, including Nup1 (Fischer et al., 2002, 2004; Faza et al., 2009; Jani et al., 2009, 2014; Ellisdon and Stewart, 2012). "
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