# Control of mating-type switching by Sir2 and condensin

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $345,341

## Abstract

Project Summary.
Since the first descriptions of mating-type switching in budding yeast approximately 40 years ago,
characterization of this process has led to numerous key advances in understanding the mechanisms of
gene silencing (heterochromatin), cell-fate determination (mating-type), and homologous recombination.
For example, the highly conserved NAD+-dependent protein deacetylase, Sir2, and other “silent
information regulator (SIR) proteins, were initially identified due to their roles in silencing the
heterochromatic HMLα and HMRa loci, which are maintained as silenced copies of the active MATα and
MATa loci, respectively. Mating-type switching occurs when a programmed dsDNA break is generated at
the MAT locus by an endonuclease called HO. The break is then repaired through homologous
recombination using either HMLα or HMRa as a template, with a strong preference for switching to the
opposite mating type. Such “donor preference” in switching is directed by a cis-acting sequence adjacent
to HMLα called the recombination enhancer (RE). Numerous chromatin factors have been implicated in
mating-type switching, but mechanisms involving chromosome structural dynamics have remained
elusive. In this proposal we investigate a newly discovered process of coordinating the “sensing” of an
HO-induced dsDNA break at the MAT locus with requisite chromosome III structural changes. Within the
RE we identified a strong binding site for Sir2, condensin, and cohibin (Lrs4/Csm1) at the promoter of a
long non-coding RNA (lncRNA) gene called RDT1. This site maintains chromosome III in a switching-
competent structural conformation. Sir2 normally represses RDT1 transcription in non-switching cells, but
is redistributed to the HO-induced break site at MAT, which activates RDT1 transcription and triggers
mating-type switching. We propose 3 specific aims that will determine not only how RDT1 lncRNA
induces switching, but also investigate the roles of condensin and cohibin in the programmed structural
reorganization of chromosome III. This provides a unique and well-defined system for elucidating
condensin function outside of mitotic chromosome compaction, something currently missing in the field.

## Key facts

- **NIH application ID:** 9924567
- **Project number:** 5R01GM127394-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jeffrey Scott Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,341
- **Award type:** 5
- **Project period:** 2018-08-13 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924567

## Citation

> US National Institutes of Health, RePORTER application 9924567, Control of mating-type switching by Sir2 and condensin (5R01GM127394-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9924567. Licensed CC0.

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