NatB domain-containing CRA-1 antagonizes hydrolase ACER-1 linking acetyl-CoA metabolism to the initiation of recombination during C. elegans meiosis.
NatB domain-containing CRA-1 antagonizes hydrolase ACER-1 linking acetyl-CoA metabolism to the initiation of recombination during C. elegans meiosis.
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DOI：
10.1371/journal.pgen.1005029
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Colaiácovo MP
中科院分区：
文献类型：
--
作者：
Gao J;Kim HM;Elia AE;Elledge SJ;Colaiácovo MP
DNA双链断裂（DSB）的形成必须发生在减数分裂期间，以确保形成交叉，这是准确的染色体分离所必需的，从而避免非整倍性。然而，DSB的形成必须受到严格的调控，以保持基因组的完整性。这种调节如何在不同的染色质结构和可接近性的背景下运作，以及它如何与代谢途径联系在一起，目前还不清楚。我们在这里表明，全球组蛋白乙酰化水平经历整个减数分裂进程的变化。此外，整体组蛋白乙酰化水平的扰动伴随着C中DSB形成频率的变化。优雅的我们提供的证据表明，组蛋白乙酰化的调节需要CRA-1，一个NatB结构域的蛋白同源的人NAA 25，控制水平的乙酰辅酶A（乙酰辅酶A）通过拮抗ACER-1，以前未知的和保守的乙酰辅酶A水解酶。CRA-1又受XND-1（一种含AT-钩的蛋白）负调控。我们建议，这个新定义的蛋白质网络连接乙酰辅酶A代谢减数分裂DSB形成通过调制全球组蛋白乙酰化。实现精确的染色体分离是任何细胞分裂过程的关键结果。程序性DNA双链断裂形成是减数分裂过程中染色体可靠分离的重要机制。这些DSB的一个子集通过同源染色体之间的遗传信息的相互交换而被修复为交叉，从而导致同源物之间的物理连接（交叉），这确保了减数分裂I时中期板处的染色体正确对齐，并且还促进了遗传多样性。这种调节如何在不同的染色质结构和可接近性的背景下运作，以及它如何与代谢途径联系在一起，目前还不清楚。在这项研究中，我们发现CRA-1，一个NatB结构域的蛋白质，促进组蛋白乙酰化，通过维持乙酰辅酶A（乙酰辅酶A）的水平，通过拮抗ACER-1，一个以前未知的和保守的乙酰辅酶A水解酶。CRA-1又受XND-1（一种含AT-钩的蛋白）负调控。我们利用这一发现来寻找乙酰辅酶A、组蛋白乙酰化和DSB形成水平之间的联系。我们确定了一种新的蛋白质网络，将DSB形成的调节与组蛋白乙酰化的全球水平的调节联系起来，并揭示了代谢与DSB形成调节之间的联系。
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. 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.
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影响因子：
11.8
作者：
Colaiácovo, MP;MacQueen, AJ;Villeneuve, AM
通讯作者：
Villeneuve, AM
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