气候变化领域集成服务门户(CCPortal): A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli

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DOI	10.1073/pnas.2026595118
	A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli
	Silas Y.; Singer E.; Das K.; Lehming N.; Pines O.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:23
英文摘要	Class-II fumarases (fumarate hydratase, FH) are dual-targeted enzymes occurring in the mitochondria and cytosol of all eukaryotes. They are essential components in the DNA damage response (DDR) and, more specifically, protect cells from DNA double-strand breaks. Similarly, the gram-positive bacterium Bacillus subtilis class-II fumarase, in addition to its role in the tricarboxylic acid cycle, participates in the DDR. Escherichia coli harbors three fumarase genes: class-I fumA and fumB and class-II fumC. Notably, class-I fumarases show no sequence similarity to class-II fumarases and are of different evolutionary origin. Strikingly, here we show that E. coli fumarase functions are distributed between class-I fumarases, which participate in the DDR, and the class-II fumarase, which participates in respiration. In E. coli, we discover that the signaling molecule, alpha-ketoglutarate (α-KG), has a function, complementing DNA damage sensitivity of fum-null mutants. Excitingly, we identify the E. coli α-KG-dependent DNA repair enzyme AlkB as the target of this interplay of metabolite signaling. In addition to α-KG, fumarate (fumaric acid) is shown to affect DNA damage repair on two different levels, first by directly inhibiting the DNA damage repair enzyme AlkB demethylase activity, both in vitro and in vivo (countering α-KG). The second is a more global effect on transcription, because fum-null mutants exhibit a decrease in transcription of key DNA damage repair genes. Together, these results show evolutionary adaptable metabolic signaling of the DDR, in which fumarases and different metabolites are recruited regardless of the evolutionary enzyme class performing the function. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AlkB; DNA damage; Fumarase; Metabolite signaling; Tricarboxylic acid cycle
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238533
作者单位	Department of Microbiology and Molecular Genetics, The Institute For Medical Reseach Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 9112102, Israel; Campus for Research Excellence and Technological Enterprise (CREATE), National University of Singapore (NUS), Hebrew University of Jerusalem (HUJ), Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138602, Singapore
推荐引用方式 GB/T 7714	Silas Y.,Singer E.,Das K.,et al. A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli[J],2021,118(23).
APA	Silas Y.,Singer E.,Das K.,Lehming N.,&Pines O..(2021).A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli.Proceedings of the National Academy of Sciences of the United States of America,118(23).
MLA	Silas Y.,et al."A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli".Proceedings of the National Academy of Sciences of the United States of America 118.23(2021).