Cell-Cycle Modulation of Transcription Termination Factor Sen1

Hannah E Mischo; Yujin Chun; Kevin M Harlen; Brendan M Smalec; Somdutta Dhir; L Stirling Churchman; Stephen Buratowski

doi:10.1016/j.molcel.2018.03.010

Cell-Cycle Modulation of Transcription Termination Factor Sen1

Mol Cell. 2018 Apr 19;70(2):312-326.e7. doi: 10.1016/j.molcel.2018.03.010. Epub 2018 Apr 12.

Authors

Hannah E Mischo¹, Yujin Chun², Kevin M Harlen³, Brendan M Smalec³, Somdutta Dhir⁴, L Stirling Churchman³, Stephen Buratowski⁵

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK; Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms EN6 3LD, UK. Electronic address: [email protected].
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK.
⁵ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

Abstract

Many non-coding transcripts (ncRNA) generated by RNA polymerase II in S. cerevisiae are terminated by the Nrd1-Nab3-Sen1 complex. However, Sen1 helicase levels are surprisingly low compared with Nrd1 and Nab3, raising questions regarding how ncRNA can be terminated in an efficient and timely manner. We show that Sen1 levels increase during the S and G2 phases of the cell cycle, leading to increased termination activity of NNS. Overexpression of Sen1 or failure to modulate its abundance by ubiquitin-proteasome-mediated degradation greatly decreases cell fitness. Sen1 toxicity is suppressed by mutations in other termination factors, and NET-seq analysis shows that its overexpression leads to a decrease in ncRNA production and altered mRNA termination. We conclude that Sen1 levels are carefully regulated to prevent aberrant termination. We suggest that ncRNA levels and coding gene transcription termination are modulated by Sen1 to fulfill critical cell cycle-specific functions.

Keywords: NNS; Nrd1-Nab3-Sen1; Sen1; cell cycle; non-coding RNA; transcription termination; ubiquitin-proteasome system.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

DNA Helicases / genetics
DNA Helicases / metabolism*
G1 Phase Cell Cycle Checkpoints*
Gene Expression Regulation, Fungal*
Microbial Viability
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Proteasome Endopeptidase Complex / metabolism
Proteolysis
RNA Helicases / genetics
RNA Helicases / metabolism*
RNA, Fungal / biosynthesis*
RNA, Fungal / genetics
RNA, Messenger / biosynthesis*
RNA, Messenger / genetics
RNA, Untranslated / biosynthesis*
RNA, Untranslated / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / growth & development
Saccharomyces cerevisiae / metabolism*
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism*
Transcription Termination, Genetic*
Ubiquitination

Substances

NAB3 protein, S cerevisiae
NRD1 protein, S cerevisiae
Nuclear Proteins
RNA, Fungal
RNA, Messenger
RNA, Untranslated
RNA-Binding Proteins
Saccharomyces cerevisiae Proteins
Proteasome Endopeptidase Complex
SEN1 protein, S cerevisiae
DNA Helicases
RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding