# Mechanism of yeast gene regulation

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2020 · $810,210

## Abstract

PROJECT SUMMARY
The mechanisms by which eukaryotes regulate gene expression are important for understanding many
complex biological phenomena including human diseases. Prevention and treatment of such diseases have
been and will continue to be improved by basic knowledge of gene regulation, especially because molecular
mechanisms of transcriptional initiation are highly conserved in eukaryotic organisms ranging from human to
yeast. This proposal will continue to investigate basic issues concerning molecular mechanisms of
transcriptional regulation, polyadenylation, and mRNA stability in yeast, by combining molecular genetic,
biochemical, functional genomic, and evolutionary approaches. Work in the first two sections will take
advantage of our novel and recently developed methodologies for measuring half-lives, structure (DREADS via
chemical probes), protein binding (CLIP-READS), and poly(A) length (A-READS) of individual mRNA 3'
isoforms. First, in the area of polyadenylation, we will A) address the mechanisms for why polyadenylation is
restricted to the 3' UTR. B) identify factors that are responsible for the wild-type poly(A) pattern, C) determine
the factors and mechanistic basis for regulated polyadenylation during the diauxic shift (and perhaps other
conditions), and D) elucidate 3'-isoform variation and regulation of poly(A) length. Second, for studies of
mRNA stabilization/destabilization elements and half-lives of 3' isoforms and, we will A) perform RNA structural
analysis during the degradation process, B) identify protein factors mediating the large differences in mRNA
isoform stabilities C) perform directed genetic experiments to address how secondary structure affects mRNA
stability, D) identify mRNA stabilization and destabilizing elements that differentially affected by environmental
conditions, and E) identify factors important for regulated mRNA half-lives, which the goal of elucidating the
mechanism of regulated mRNA stability. Third, we will address a variety of issues concerning transcriptional
regulation including A) the nature of the transcriptional activator that coordinately regulates ribosomal protein
gene expression via recruitment of TFIID, B) determining the mechanistic basis of why activator proteins do not
function when bound downstream of or far away from the core promoter, C) DNA looping mechanisms,
particularly the nature of the protein-protein interactions needed to form the loop and to stimulate transcription,
and D) examining the role of histone acetylation in transcriptional regulation by generating non-acetylable
derivatives of the 4 histones. Fourth, we will use a novel conceptual and experimental approach to distinguish
biological function from biological noise that is based on a comparison of physiological responses, RNA and
transcription factor binding profiles, and effects of mutations in yeast species of varying evolutionary distance.
We will explicitly measure biological noise by making functional measu...

## Key facts

- **NIH application ID:** 9922945
- **Project number:** 5R35GM131801-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** KEVIN STRUHL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $810,210
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922945

## Citation

> US National Institutes of Health, RePORTER application 9922945, Mechanism of yeast gene regulation (5R35GM131801-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9922945. Licensed CC0.

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