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2.
iScience ; 25(11): 105410, 2022 Nov 18.
Article in English | MEDLINE | ID: mdl-36388960

ABSTRACT

Deletion of genes encoding ribosomal proteins extends lifespan in yeast. This increases translation of the functionally conserved transcription factor Gcn4, and lifespan extension in these mutants is GCN4-dependent. Gcn4 is also translationally upregulated by uncharged tRNAs, as are its C aenorhabditis elegans and mammalian functional orthologs. Here, we show that cytosolic tRNA synthetase inhibitors upregulate Gcn4 translation and extend yeast lifespan in a Gcn4-dependent manner. This cytosolic tRNA synthetase inhibitor is also able to extend the lifespan of C. elegans in an atf-4-dependent manner. We show that mitochondrial tRNA synthetase inhibitors greatly extend the lifespan of C. elegans, and this depends on atf-4. This suggests that perturbations of both cytosolic and mitochondrial translation may act in part via the same downstream pathway. These findings establish GCN4 orthologs as conserved longevity factors and, as long-lived mice exhibit elevated ATF4, leave open the possibility that tRNA synthetase inhibitors could also extend lifespan in mammals.

4.
Crit Rev Oncog ; 27(2): 17-33, 2022.
Article in English | MEDLINE | ID: mdl-36734870

ABSTRACT

DNA polymerase beta (Pol ß) is a 39 kD vertebrate polymerase that lacks proofreading ability, yet still maintains a moderate fidelity of DNA synthesis. Pol ß is a key enzyme that functions in the base excision repair and non-homologous end joining pathways of DNA repair. Mechanisms of fidelity for Pol ß are still being elucidated but are likely to involve dynamic conformational motions of the enzyme upon its binding to DNA and deoxynucleoside triphosphates. Recent studies have linked germline and somatic variants of Pol ß with cancer and autoimmunity. These variants induce genomic instability by a number of mechanisms, including error-prone DNA synthesis and accumulation of single nucleotide gaps that lead to replication stress. Here, we review the structure and function of Pol ß, and we provide insights into how structural changes in Pol ß variants may contribute to genomic instability, mutagenesis, disease, cancer development, and impacts on treatment outcomes.


Subject(s)
DNA Polymerase beta , Neoplasms , Humans , DNA Polymerase beta/genetics , DNA Polymerase beta/chemistry , DNA Polymerase beta/metabolism , DNA Replication/genetics , DNA/genetics , DNA Repair/genetics , Genomic Instability , Neoplasms/genetics
5.
Nat Commun ; 9(1): 1487, 2018 04 16.
Article in English | MEDLINE | ID: mdl-29662074

ABSTRACT

Within cells, motor and non-motor microtubule-associated proteins (MAPs) simultaneously converge on the microtubule. How the binding activities of non-motor MAPs are coordinated and how they contribute to the balance and distribution of motor transport is unknown. Here, we examine the relationship between MAP7 and tau owing to their antagonistic roles in vivo. We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. MAP7 promotes kinesin-based transport in vivo and strongly recruits kinesin-1 to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. Both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs differentially control distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of motor activity.


Subject(s)
Dyneins/genetics , Kinesins/genetics , Microtubules/metabolism , Neurons/metabolism , Tubulin/genetics , tau Proteins/genetics , Animals , Binding, Competitive , Biological Transport , Drosophila melanogaster , Dyneins/metabolism , Gene Expression , Humans , Kinesins/metabolism , Mice , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Microtubules/ultrastructure , Neurons/ultrastructure , Primary Cell Culture , Protein Binding , Swine , Tubulin/metabolism , tau Proteins/metabolism
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