Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation
Joyce Yip,
Suqing Wang,
Jasper Tan,
Teck Kwang Lim,
Qingsong Lin,
Zhang Yu,
Ofri Karmon,
Ophry Pines,
Norbert Lehming
Affiliations
Joyce Yip
Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore
Suqing Wang
Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore
Jasper Tan
Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore
Teck Kwang Lim
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
Qingsong Lin
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
Zhang Yu
Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel; CREATE-NUS-HUJ Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Ofri Karmon
Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel; CREATE-NUS-HUJ Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Ophry Pines
Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel; CREATE-NUS-HUJ Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Corresponding author
Norbert Lehming
Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore; Corresponding author
Summary: The Krebs cycle enzyme fumarase, which has been identified as a tumor suppressor, is involved in the deoxyribonucleic acid (DNA) damage response (DDR) in human, yeast, and bacterial cells. We have found that the overexpression of the cysteine desulfurase Nfs1p restores DNA repair in fumarase-deficient yeast cells. Nfs1p accumulates inactivating post-translational modifications in yeast cells lacking fumarase under conditions of DNA damage. Our model is that in addition to metabolic signaling of the DDR in the nucleus, fumarase affects the DDR by protecting the desulfurase Nfs1p in mitochondria from modification and inactivation. Fumarase performs this protection by directly binding to Nfs1p in mitochondria and enabling, the maintenance, via metabolism, of a non-oxidizing environment in mitochondria. Nfs1p is required for the formation of Fe–S clusters, which are essential cofactors for DNA repair enzymes. Thus, we propose that the overexpression of Nfs1p overcomes the lack of fumarase by enhancing the activity of DNA repair enzymes.
