NatB Domain-Containing CRA-1 Antagonizes Hydrolase ACER-1 Linking Acetyl-CoA Metabolism to the Initiation of Recombination during C . elegans Meiosis

abstract: ...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.

...PLoS Genet PLoS Genet plos plosgen PLoS Genetics 1553-7390 1553-7404 Public Library of Science San Francisco, CA USA 25768301 4359108 10.1371/journal.pgen.1005029 PGENETICS-D-14-03109 Research Article NatB Domain-Containing CRA-1 Antagonizes Hydrolase ACER-1 Linking Acetyl-CoA Metabolism to the Initiation of Recombination during C . elegans Meiosis Acetyl-CoA Levels Link Histone Acetylation to DSBs Gao Jinmin Kim Hyun-Min Elia Andrew E. Elledge Stephen J. Colaicovo Monica P. * Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America Jantsch Verena Editor University of Vienna, AUSTRIA The authors have declared that no competing interests exist. Conceived and designed the experiments: JG MPC. Performed the experiments: JG AEE. Analyzed the data: JG MPC. Contributed reagents/materials/analysis tools: HMK SJE. Wrote the paper: JG MPC. * E-mail: mcolaiacovo@genetics.med.harvard.edu 13 3 2015 3 2015 11 3 e1005029 18 11 2014 27 1 2015 2015 Gao et al 2015 Gao et al This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. 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

... regulating acetylation of lysine 5 on histone H2A (H2AK5ac) and the global distribution of crossovers, but it affects DSB formation only on the X chromosome [ 29 ]. CRA-1 is a NatB domain-containing protein conserved in yeast, worms, flies, zebrafish and mammals, previously shown to promote chromosome synapsis and crossover formation preferentially on the autosomes during meiosis in C . elegans [ 30 ]. NAA25, the CRA-1 homolog in humans, has been suggested to be the non-catalytic subunit of the NatB N

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Gene: NAA25 - N(alpha)-acetyltransferase 25, NatB auxiliary subunit - (NCBI)

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