Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins
- Indian Institute of Science Bangalore, India
Abstract
Reactive carbonyl species (RCS) such as methylglyoxal and glyoxal are potent glycolytic intermediates that extensively damage cellular biomolecules leading to genetic aberration and protein misfolding. Hence, RCS levels are crucial indicators in the progression of various pathological diseases. Besides the glyoxalase system, emerging studies report highly conserved DJ-1 superfamily proteins as critical regulators of RCS. DJ-1 superfamily proteins, including the human DJ-1, a genetic determinant of Parkinson's disease, possess diverse physiological functions paramount for combating multiple stressors. Although S. cerevisiae retains four DJ-1 orthologs (Hsp31, Hsp32, Hsp33, and Hsp34), their physiological relevance and collective requirement remain obscure. Here, we report for the first time that the yeast DJ-1 orthologs function as novel enzymes involved in the preferential scavenge of glyoxal and methylglyoxal, toxic metabolites, and genotoxic agents. Their collective loss stimulates chronic glycation of the proteome, and nucleic acids, inducing spectrum of genetic mutations and reduced mRNA translational efficiency. Furthermore, the Hsp31 paralogs efficiently repair severely glycated macromolecules derived from carbonyl modifications. Also, their absence elevates DNA damage response, making them vulnerable to various genotoxins. Interestingly, yeast DJ-1 orthologs preserve functional mitochondrial content, maintain ATP levels, and redistribute into mitochondria to alleviate the glycation damage of macromolecules. Together, our study uncovers a novel glycation repair pathway in S. cerevisiae and a possible neuroprotective mechanism of how hDJ-1 confers mitochondrial health during glycation toxicity.
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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all the Figures and Figure Supplements
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Author details
Funding
Science and Engineering Research Board (CRG/2018/001988)
- Patrick D'Silva
Department of Science and Technology, Ministry of Science and Technology, India (SR/FST/LSII045/2016-G)
- Patrick D'Silva
Department of Biotechnology, Ministry of Science and Technology, India (BT/PR27952/IN/22/212/2018)
- Patrick D'Silva
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Susarla et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins
eLife 12:e88875.
https://doi.org/10.7554/eLife.88875
