@article {2150, title = {The Rad53-Spt21 and Tel1 axes couple glucose tolerance to histone dosage and subtelomeric silencing.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 19}, pages = {4154}, abstract = {

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21 on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1 and Rpd3 activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.

}, keywords = {Acetylation, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Damage, DNA Repair, Gene Silencing, Glucose, Histone Deacetylases, Histones, Intracellular Signaling Peptides and Proteins, Mutation, Phosphorylation, Protein-Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Serine, Telomere, Transcription Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17961-4}, author = {Bruhn, Christopher and Ajazi, Arta and Ferrari, Elisa and Lanz, Michael Charles and Batrin, Renaud and Choudhary, Ramveer and Walvekar, Adhish and Laxman, Sunil and Longhese, Maria Pia and Fabre, Emmanuelle and Smolka, Marcus Bustamente and Foiani, Marco} } @article {1583, title = {Mutation burden profile in familial Alzheimer{\textquoteright}s disease cases from India.}, journal = {Neurobiol Aging}, volume = {64}, year = {2018}, month = {2018 04}, pages = {158.e7-158.e13}, abstract = {

This study attempts to identify coding risk variants in genes previously implicated in Alzheimer{\textquoteright}s disease (AD) pathways, through whole-exome sequencing of subjects (N\ = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg \> tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

}, keywords = {Aged, Alzheimer Disease, Amyloid beta-Protein Precursor, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, India, LDL-Receptor Related Proteins, Membrane Transport Proteins, Middle Aged, Mutation, Presenilin-1, Risk, Signal Transduction, Tissue Plasminogen Activator, Whole Exome Sequencing}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2017.12.002}, author = {Syama, Adhikarla and Sen, Somdatta and Kota, Lakshmi Narayanan and Viswanath, Biju and Purushottam, Meera and Varghese, Mathew and Jain, Sanjeev and Panicker, Mitradas M and Mukherjee, Odity} } @article {1203, title = {Structural and functional studies of ferredoxin and oxygenase components of 3-nitrotoluene dioxygenase from Diaphorobacter sp. strain DS2.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0176398}, abstract = {

3-nitrotoluene dioxygenase (3NTDO) from Diaphorobacter sp. strain DS2 catalyses the conversion of 3-nitrotoluene (3NT) into a mixture of 3- and 4-methylcatechols with release of nitrite. We report here, X-ray crystal structures of oxygenase and ferredoxin components of 3NTDO at 2.9 {\r A} and 2.4 {\r A}, respectively. The residues responsible for nitrite release in 3NTDO were further probed by four single and two double mutations in the catalytic site of α-subunit of the dioxygenase. Modification of Val 350 to Phe, Ile 204 to Ala, and Asn258 to Val by site directed mutagenesis resulted in inactive enzymes revealing the importance of these residues in catalysis. Docking studies of meta nitrotoluene to the active site of 3NTDO suggested possible orientations of binding that favor the formation of 3-methylcatechol (3MC) over 4-methylcatechol energetically. The electron transfer pathway from ferredoxin subunit to the active site of the oxygenase subunit is also proposed.

}, keywords = {Catalytic Domain, Comamonadaceae, Crystallography, X-Ray, Ferredoxins, Molecular Docking Simulation, Mutation, Oxygenases, Substrate Specificity, Toluene}, issn = {1932-6203}, doi = {10.1371/journal.pone.0176398}, author = {Kumari, Archana and Singh, Deepak and Ramaswamy, S and Ramanathan, Gurunath} }