Academic journal article Genetics

Insight into the RNA Exosome Complex through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

Academic journal article Genetics

Insight into the RNA Exosome Complex through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

Article excerpt

THE RNA exosome is an evolutionarily conserved ribonuclease complex that is responsible for several essential RNA processing and degradation steps (Mitchell et al. 1997; Allmang et al. 1999; Schneider and Tollervey 2013). Major exosome substrates include mRNA, rRNA, and small RNAs. In addition to degrading aberrant and unneeded transcripts, the RNA exosome also trims precursor RNAs, including 5.8S rRNA (Mitchell et al. 1996). The RNA exosome thus plays critical roles in both RNA degradation and maturation.

The subunits of the RNA exosome complex are evolutionarily conserved and many were first identified in Saccharomyces cerevisiae in a screen for ribosomal RNA processing (rrp) mutants (Mitchell et al. 1996, 1997; Allmang et al. 1999). S. cerevisiae Rrp subunits correspond to human EXOSC subunits. The functions of the RNA exosome have been extensively characterized in budding yeast (Sloan et al. 2012), and many are conserved in humans (Schilders et al. 2005; Staals et al. 2010; Lubas et al. 2011, 2015). Within the RNA exosome, six subunits comprise a core ring, and three putative RNA-binding subunits, including EXOSC3, form a cap that interacts with the core ring on one side of the complex (Figure 1A). The catalytic DIS3 subunit, which possesses both endo and exoribonuclease activities (Dziembowski et al. 2007; Lebreton et al 2008; Schaeffer et al. 2009), associates with the opposite side of the core ring from the cap (Figure 1A) (Malet et al 2010; Staals et al. 2010; Tomecki et al 2010; Makino et al 2013). RNA substrates can be threaded through the central channel of the core ring from the EXOSC3/cap side (Liu et al 2006; Bonneau et al. 2009; Malet et al. 2010; Makino et al 2013). Additional RNA entry points have also been identified (Liu et al. 2014; Wasmuth et al. 2014; Han and van Hoof 2016) that could provide insight into how the RNA exosome balances precise processing and complete degradation of RNA.

The RNA exosome is present in both the nucleus and the cytoplasm. Nuclear and cytoplasmic RNA exosomes also require specific exosome cofactors (Butler and Mitchell 2010; Schaeffer et al. 2010), which help to guide the degradation and/or processing of specific RNAs. In particular, the cytoplasmic cofactor, the SKI complex, is required for all known cytoplasmic functions of the RNA exosome, but not for its nuclear functions (Jacobs Anderson and Parker 1998; van Hoof et al. 2000). Importantly, exosome cofactors characterized in budding yeast (Jacobs Anderson and Parker 1998; Allmang et al. 1999; Brown et al. 2000; van Hoof et al. 2000; LaCava et al. 2005; Vasiljeva and Buratowski 2006), are conserved in Metazoa, and possess conserved functions in humans (Schilders et al. 2007; Shcherbik et al. 2010; Lubas et al. 2011; Kowalinski et al. 2016).

Defects in the RNA exosome, and exosome cofactors, have been implicated in several genetic diseases. Mutations in SKI complex genes have been linked to tricho-hepato-enteric (THE) syndrome, which causes intestinal failure (Hartley et al. 2010; Fabre et al 2012, 2013). In addition, mutations in the DIS3 catalytic subunit gene have been implicated in multiple myeloma (Chapman et al. 2011; Tomecki et al 2013; Robinson et al 2015). Recently mutations in genes encoding structural exosome subunits have been linked to neurological diseases (Wan et al 2012; Boczonadi etal. 2014; Di Donato etal. 2016). Mutations in the gene encoding the RNA exosome cap subunit, EXOSC3 (Figure 1, B and C), have been linked to pontocerebellar hypoplasia type 1b (PCH1b) (Wan et al. 2012). PCH1b does not appear to share common traits with THE syndrome or multiple myeloma. Instead, PCH1b patients exhibit significant atrophy of the pons and cerebellum, Purkinje cell abnormalities, and degeneration of spinal motor neurons (Wan et al. 2012). PCH1b patients also show microcephaly, muscle atrophy, and growth and developmental retardation (Rudnik-Schoneborn et al 2013). Most PCH1b patients do not live past childhood. …

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