Post-translational Modifications of Fumarase Regulate its Enzyme Activity and Function in Respiration and the DNA Damage Response

Wang, Haihui; Ramamurthy, Dharanidharan; Tan, Jasper; Liu, Jingyan; Yip, Joyce; Chua, Andrea; Zhang, Yu; Lim, Teck Kwang; Lin, Qingsong; Pines, Ophry; Lehming, Norbert

doi:10.1016/j.jmb.2020.09.021

Cited by 5 publications

(4 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ubiquitination of lysine 79 in fumarase inhibits its function in the TCA cycle and DNA damage repair. This report reveals how posttranslational modifications affect fumarase function ( Wang S. et al, 2020 ). Tumor cells use Gln in the TCA cycle to maintain biosynthesis and support rapid growth and proliferation.…”

Section: Ubiquitination Sumoylation and Glucose Metabolism In Cancermentioning

confidence: 80%

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

Zhu

Peng

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Ubiquitination and SUMOylation, which are posttranslational modifications, play prominent roles in regulating both protein expression and function in cells, as well as various cellular signal transduction pathways. Metabolic reprogramming often occurs in various diseases, especially cancer, which has become a new entry point for understanding cancer mechanisms and developing treatment methods. Ubiquitination or SUMOylation of protein substrates determines the fate of modified proteins. Through accurate and timely degradation and stabilization of the substrate, ubiquitination and SUMOylation widely control various crucial pathways and different proteins involved in cancer metabolic reprogramming. An understanding of the regulatory mechanisms of ubiquitination and SUMOylation of cell proteins may help us elucidate the molecular mechanism underlying cancer development and provide an important theory for new treatments. In this review, we summarize the processes of ubiquitination and SUMOylation and discuss how ubiquitination and SUMOylation affect cancer metabolism by regulating the key enzymes in the metabolic pathway, including glucose, lipid and amino acid metabolism, to finally reshape cancer metabolism.

show abstract

Section: Ubiquitination Sumoylation and Glucose Metabolism In Cancermentioning

confidence: 80%

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

Zhu

Peng

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…The absence of functional fumarase leads to the accumulation of fumarate in the cell (Yang et al, 2014). Fumarase and other TCA-related intermediates metabolically signal the DDR in human, yeast, and bacterial cells (Yogev et al, 2010;Singer et al, 2017;Wang et al, 2020;Silas et al, 2021). In the context of this study, it is worth mentioning that the reaction between fumarate and cysteine residues of proteins can lead to a post-translational modification known as succination (Blatnik et al, 2008).…”

Section: Introductionmentioning

confidence: 95%

“…NFS1 genes that contained more than one mutation were sub-cloned in order to determine the functionally relevant mutation. The TRP1-marked multi-copy vector PactT424-MBP expressing MBP fusions from the ACT1 promoter/terminator cassette was generated by amplifying MBP with the primers listed in Table S2 and cloning it into PactT424 (Wang et al, 2020). The mutations mimicking the observed PTMs were generated by sequential PCR with the primers listed in Table S5.…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Altered interactions in protein complexes underlie almost all phenomena in biology, but they are particularly important in cancer signaling, which maintains tumor growth and metastatic behavior. PS changes in signaling complexes that promote cancer growth arise from mutations [34], posttranslational modifications (PTMs), particularly methylation [35,36] and phosphorylation [37], as well as from other PTMs such as deamidation, ubiquitination and succination [38].…”

Section: Phenotypic Switching In Protein Interactionsmentioning

confidence: 99%

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Ladias,

Papakotoulas,

Papaioannou

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

View full text Add to dashboard Cite

Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.

show abstract

Post-translational Modifications of Fumarase Regulate its Enzyme Activity and Function in Respiration and the DNA Damage Response

Cited by 5 publications

References 31 publications

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Contact Info

Product

Resources

About