Article

FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2

Howard Hughes Medical Institute.
Genes & development (Impact Factor: 12.64). 12/2012; 26(24):2690-5. DOI: 10.1101/gad.204602.112
Source: PubMed

ABSTRACT Mutations in the RNA-binding protein FUS (fused in sarcoma)/TLS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the normal role of FUS is incompletely understood. We found that FUS binds the C-terminal domain (CTD) of RNA polymerase II (RNAP2) and prevents inappropriate hyperphosphorylation of Ser2 in the RNAP2 CTD at thousands of human genes. The loss of FUS leads to RNAP2 accumulation at the transcription start site and a shift in mRNA isoform expression toward early polyadenylation sites. Thus, in addition to its role in alternative RNA splicing, FUS has a general function in orchestrating CTD phosphorylation during RNAP2 transcription.

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    • "Thus, altered ribostasis can alter both the biogenesis and function of mRNAs, potentially creating a positive-feedback loop in which abnormal RNAs and altered protein production lead to more misregulation of cellular processes, eventually leading to systemic inflammatory signaling and cell death. In addition, aberrant mRNP aggregates are expected to influence other aspects of RNA metabolism, as some of the aggregated proteins (e.g., FUS or TDP-43) can be required for transcription and/or small nuclear ribonucleic particles (snRNP) assembly (Ishihara et al., 2013; Schwartz et al., 2012). Aberrant mRNP aggregates are also likely to alter cell survival by affecting signaling pathways. "
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    • "Although the primary result of this paper is that RNA stimulates FUS assembly, an important question remaining is whether fibrous assemblies contribute to FUS-RNAP2 interactions in vivo. FUS affects RNAP2 recruitment, the efficiency of transcription, and the phosphorylation status on the CTD of RNAP2 (Yang et al., 2000; Schwartz et al., 2012, Kwon et al., 2013). An attractive model is that the efficiency of CTD recruitment to a FUS fibrous assembly would localize the polymerase to a greater extent than single FUS-CTD interactions. "
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