NatB domain-containing CRA-1 antagonizes hydrolase ACER-1 linking acetyl-CoA metabolism to the initiation of recombination during C. elegans meiosis
| Autor: | Hyun-Min Kim, Andrew E. H. Elia, Jinmin Gao, Monica P. Colaiácovo, Stephen J. Elledge |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
X Chromosome lcsh:QH426-470 SAP30 Acetyl-CoA Hydrolase Chromosome segregation Histones 03 medical and health sciences 0302 clinical medicine Acetyl Coenzyme A Genetics Homologous chromosome Histone code Animals DNA Breaks Double-Stranded Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics 030304 developmental biology Recombination Genetic 0303 health sciences biology Acetylation biology.organism_classification Chromatin lcsh:Genetics Histone Biochemistry biology.protein 030217 neurology & neurosurgery Research Article |
| Zdroj: | PLoS Genetics, Vol 11, Iss 3, p e1005029 (2015) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | The formation of DNA double-strand breaks (DSBs) must take place during meiosis to ensure the formation of crossovers, which are required for accurate chromosome segregation, therefore avoiding aneuploidy. However, DSB formation must be tightly regulated to maintain genomic integrity. How this regulation operates in the context of different chromatin architectures and accessibility, and how it is linked to metabolic pathways, is not understood. We show here that global histone acetylation levels undergo changes throughout meiotic progression. Moreover, perturbations to global histone acetylation levels are accompanied by changes in the frequency of DSB formation in C. elegans. We provide evidence that the regulation of histone acetylation requires CRA-1, a NatB domain-containing protein homologous to human NAA25, which controls the levels of acetyl-Coenzyme A (acetyl-CoA) by antagonizing ACER-1, a previously unknown and conserved acetyl-CoA hydrolase. CRA-1 is in turn negatively regulated by XND-1, an AT-hook containing protein. We propose that this newly defined protein network links acetyl-CoA metabolism to meiotic DSB formation via modulation of global histone acetylation. Author Summary Achieving accurate chromosome segregation is a critical outcome for any cell division process. Programmed DNA double-strand break formation is a central mechanism set in place to promote faithful chromosome segregation during meiosis. A subset of these DSBs is repaired as crossovers via reciprocal exchange of genetic information between homologous chromosomes resulting in physical attachments (chiasmata) between homologs, which ensure proper chromosome alignment at the metaphase plate at meiosis I, and also promote genetic diversity. How this regulation operates in the context of different chromatin architectures and accessibility, and how it is linked to metabolic pathways, is not understood. In this study, we found that CRA-1, a NatB domain-containing protein, promotes histone acetylation by maintaining the levels of acetyl-Coenzyme A (acetyl-CoA) through antagonizing ACER-1, a previously unknown and conserved acetyl-CoA hydrolase. CRA-1 is in turn negatively regulated by XND-1, an AT-hook containing protein. We leveraged this discovery to find a connection between the levels of acetyl-CoA, histone acetylation and DSB formation. We identified a novel protein network that links the regulation of DSB formation to the modulation of global levels of histone acetylation, and revealed a link between metabolism and the regulation of DSB formation. |
| Databáze: | OpenAIRE |
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