Hst3 is turned over by a replication stress-responsive SCF(Cdc4) phospho-degron
Ellen R Edenberg1, Ajay A Vashisht, Benjamin R Topacio
1Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
Summary
The histone deacetylase Hst3 is regulated by the SCF(Cdc4) ubiquitin ligase. Its turnover increases during replication stress, controlled by Mck1 and Rad53, ensuring genomic stability.
Area of Science:
- Epigenetics and Chromatin Biology
- Molecular and Cell Biology
- DNA Damage and Repair
Background:
- Histone H3K56 acetylation is a critical chromatin marker regulated by the histone deacetylase Hst3.
- Proper H3K56 acetylation is essential for DNA replication, genomic stability, chromatin assembly, and DNA damage response.
- Dysregulation of H3K56 acetylation, leading to its loss, results in genomic instability.
Purpose of the Study:
- To investigate the posttranscriptional regulation of Hst3, a key enzyme controlling H3K56 acetylation.
- To elucidate the mechanisms by which Hst3 is targeted for degradation and how this process is influenced by cellular stress.
Main Methods:
- Investigated Hst3 protein turnover using ubiquitin-proteasome system components, including the SCF(Cdc4) ubiquitin ligase.
- Analyzed the role of specific phosphorylation sites within the Hst3 degron.
- Examined the impact of replication stress and the involvement of DNA damage response pathways (Rad53, Mck1) on Hst3 turnover.
Main Results:
- Hst3 is targeted for degradation by the SCF(Cdc4) ubiquitin ligase following phosphorylation of a multisite degron.
- Hst3 turnover is significantly increased in response to replication stress in a Rad53-dependent manner.
- Mck1 activity promotes Hst3 turnover under both normal cell cycle conditions and during replication stress.
Conclusions:
- Hst3 degradation is tightly regulated by phosphorylation-dependent targeting to the SCF(Cdc4) complex.
- The Hst3 turnover mechanism, involving specific phospho-degrons, is crucial for maintaining genomic stability, particularly under replication stress.
- Understanding Hst3 regulation provides insights into maintaining chromatin integrity and cellular response to DNA damage.
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