Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins
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. Besi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88875 |
| _version_ | 1797742265414713344 |
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| author | Gautam Susarla Priyanka Kataria Amrita Kundu Patrick D'Silva |
| author_facet | Gautam Susarla Priyanka Kataria Amrita Kundu Patrick D'Silva |
| author_sort | Gautam Susarla |
| collection | DOAJ |
| description | 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 cells 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. |
| first_indexed | 2024-03-12T14:38:28Z |
| format | Article |
| id | doaj.art-c046b832f2944f09a24f49781a546297 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T14:38:28Z |
| publishDate | 2023-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c046b832f2944f09a24f49781a5462972023-08-16T17:00:33ZengeLife Sciences Publications LtdeLife2050-084X2023-08-011210.7554/eLife.88875Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteinsGautam Susarla0https://orcid.org/0000-0002-3798-749XPriyanka Kataria1https://orcid.org/0000-0003-1860-4286Amrita Kundu2https://orcid.org/0000-0002-1499-7564Patrick D'Silva3https://orcid.org/0000-0002-1619-5311Department of Biochemistry, Indian Institute of Science, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, IndiaReactive 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 cells 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.https://elifesciences.org/articles/88875yeast Hsp31DJ-1 family proteinsDNA glycationdeglycation repairmitochondrial glycationmitochondrial dysfunction |
| spellingShingle | Gautam Susarla Priyanka Kataria Amrita Kundu Patrick D'Silva Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins eLife yeast Hsp31 DJ-1 family proteins DNA glycation deglycation repair mitochondrial glycation mitochondrial dysfunction |
| title | Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| title_full | Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| title_fullStr | Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| title_full_unstemmed | Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| title_short | Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| title_sort | saccharomyces cerevisiae dj 1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins |
| topic | yeast Hsp31 DJ-1 family proteins DNA glycation deglycation repair mitochondrial glycation mitochondrial dysfunction |
| url | https://elifesciences.org/articles/88875 |
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