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180


Bacterial Nitric Oxide Extends the Lifespan of C. elegans

Gusarov, Ivan; Gautier, Laurent; Smolentseva, Olga; Shamovsky, Ilya; Eremina, Svetlana; Mironov, Alexander; Nudler, Evgeny
Nitric oxide (NO) is an important signaling molecule in multicellular organisms. Most animals produce NO from L-arginine via a family of dedicated enzymes known as NO synthases (NOSes). A rare exception is the roundworm Caenorhabditis elegans, which lacks its own NOS. However, in its natural environment, C. elegans feeds on Bacilli that possess functional NOS. Here, we demonstrate that bacterially derived NO enhances C. elegans longevity and stress resistance via a defined group of genes that function under the dual control of HSF-1 and DAF-16 transcription factors. Our work provides an example of interspecies signaling by a small molecule and illustrates the lifelong value of commensal bacteria to their host.
PMID: 23415229
ISSN: 0092-8674
CID: 223252

The RNA polymerase bridge helix YFI motif in catalysis, fidelity and translocation

Nedialkov, Yuri A; Opron, Kristopher; Assaf, Fadi; Artsimovitch, Irina; Kireeva, Maria L; Kashlev, Mikhail; Cukier, Robert I; Nudler, Evgeny; Burton, Zachary F
The bridge alpha-helix in the beta' subunit of RNA polymerase (RNAP) borders the active site and may have roles in catalysis and translocation. In Escherichia coli RNAP, a bulky hydrophobic segment near the N-terminal end of the bridge helix is identified (beta' 772-YFI-774; the YFI motif). YFI is located at a distance from the active center and adjacent to a glycine hinge (beta' 778-GARKG-782) involved in dynamic bending of the bridge helix. Remarkably, amino acid substitutions in YFI significantly alter intrinsic termination, pausing, fidelity and translocation of RNAP. F773V RNAP largely ignores the lambda tR2 terminator at 200muM NTPs and is strongly reduced in lambda tR2 recognition at 1muM NTPs. F773V alters RNAP pausing and backtracking and favors misincorporation. By contrast, the adjacent Y772A substitution increases fidelity and exhibits other transcriptional defects generally opposite to those of F773V. All atom molecular dynamics simulation revealed two separate functional connections emanating from YFI explaining the distinct effects of substitutions: Y772 communicates with the active site through the link domain in the beta subunit, whereas F773 communicates through the fork domain in the beta subunit. I774 interacts with the F-loop, which also contacts the glycine hinge of the bridge helix. These results identified negative and positive circuits coupled at YFI and employed for regulation of catalysis, elongation, termination and translocation.
PMCID:3619131
PMID: 23202476
ISSN: 0006-3002
CID: 213962

Looking for a promoter in 3D

Svetlov, Vladimir; Nudler, Evgeny
PMID: 23381630
ISSN: 1545-9985
CID: 218052

A decade of riboswitches

Serganov, Alexander; Nudler, Evgeny
Riboswitches were discovered in 2002 in bacteria as RNA-based intracellular sensors of vitamin derivatives. During the last decade, naturally occurring RNA sensor elements have been found to bind a range of small metabolites and ions and to exert regulatory control of transcription, translation, splicing, and RNA stability. Extensive biochemical, structural, and genetic studies have established the basic principles underpinning riboswitch function in all three kingdoms of life with implications for developing antibiotics, designing new molecular sensors, and integrating riboswitches into synthetic circuits.
PMCID:4215550
PMID: 23332744
ISSN: 0092-8674
CID: 213732

Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

Bobkova, Natalia; Guzhova, Irina; Margulis, Boris; Nesterova, Inna; Medvedinskaya, Natalia; Samokhin, Alexander; Alexandrova, Irina; Garbuz, David; Nudler, Evgeny; Evgen'ev, Michael
Numerous epidemiological studies have established acute brain injury as one of the major risk factors for the Alzheimer's disease (AD). However, the lack of animal models of AD-like degeneration triggered by a defined injury hampered the development of adequate therapies. Here we report that the surgical damage of the olfactory bulbs triggers the development of several pathologies, including amyloid-beta accumulation and strong decrease of neuron density in the cortex and hippocampus as well as significant disturbance of spatial memory. Characteristically, these harmful consequences of the olfactory bulbectomy (OBX) have a peculiar dynamics in time with maximal manifestation in periods of 1-1.5 months and 8 months after the surgery and, hence, exhibit biphasic pattern with almost complete recovery period taking place at 5-6 months after the operation. The quantitative determination of endogenous inducible form of Hsp70 in different brain areas of OBX mice demonstrated characteristic fluctuations of Hsp70 levels depending on the time after the operation and age of mice. Interestingly, maximal induction of Hsp70 synthesis in the hippocampus exhibits clear-cut coincidence with the recovery period in OBX animals. The observed correlation enables to suggest curing effect of Hsp70 synthesis at an earlier period of pathology development and establishes it as a possible therapeutic agent for secondary grave consequences of brain injury, such as AD-like degeneration, for which neuroprotective therapy is urgently needed.
PMCID:3508132
PMID: 22836235
ISSN: 1355-8145
CID: 205622

Basic mechanism of transcription by RNA polymerase II

Svetlov, Vladimir; Nudler, Evgeny
RNA polymerase II-like enzymes carry out transcription of genomes in Eukaryota, Archaea, and some viruses. They also exhibit fundamental similarity to RNA polymerases from bacteria, chloroplasts, and mitochondria. In this review we take an inventory of recent studies illuminating different steps of basic transcription mechanism, likely common for most multi-subunit RNA polymerases. Through the amalgamation of structural and computational chemistry data we attempt to highlight the most feasible reaction pathway for the two-metal nucleotidyl transfer mechanism, and to evaluate the way catalysis can be linked to translocation in the mechano-chemical cycle catalyzed by RNA polymerase II. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation.
PMCID:3545073
PMID: 22982365
ISSN: 0006-3002
CID: 213252

Erratum: Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice (Cell Stress and Chaperones (2013) 18 (119) DOI 10.1007/s12192-012-0359-x)

Bobkova, N; Guzhova, I; Margulis, B; Nesterova, I; Medvinskaya, N; Samokhin, A; Alexandrova, I; Garbuz, D; Nudler, E; Evgen'ev, M
EMBASE:52289514
ISSN: 1355-8145
CID: 3924502

H2S as a bacterial defense against antibiotics

Chapter by: Luhachack, L; Nudler, E
in: Hydrogen Sulfide and its Therapeutic Applications by
pp. 173-180
ISBN: 9783709115503
CID: 1774262

RNA polymerase stalls in a post-translocated register and can hyper-translocate

Nedialkov, Yuri A; Nudler, Evgeny; Burton, Zachary F
Exonuclease (Exo) III was used to probe translocation states of RNA polymerase (RNAP) ternary elongation complexes (TECs). Escherichia coli RNAP stalls primarily in a post-translocation register that makes relatively slow excursions to a hyper-translocated state or to a pre-translocated state. Tagetitoxin (TGT) strongly inhibits hyper-translocation and inhibits backtracking, so, as indicated by Exo III mapping, TGT appears to stabilize both the pre- and probably a partially post-translocation state of RNAP. Because the pre-translocated to post-translocated transition is slow at many template positions, these studies appear inconsistent with a model in which RNAP makes frequent and rapid (i.e., millisecond phase) oscillations between pre- and post-translocation states. Nine nucleotides (9-nt) and 10-nt TECs, and TECs with longer nascent RNAs, have distinct translocation properties consistent with a 9-10 nt RNA/DNA hybrid. RNAP mutant proteins in the bridge helix and trigger loop are identified that inhibit or stimulate forward and backward translocation.
PMCID:3632624
PMID: 23132506
ISSN: 2154-1272
CID: 231682

Unfolding the Bridge between Transcription and Translation

Svetlov, Vladimir; Nudler, Evgeny
Transcription antiterminator RfaH alternates between closed (inactive) and open (activated) conformation. In this issue of Cell, Burmann et al. show that opening is accompanied by dramatic all-alpha to all-beta refolding of its C-terminal domain. Each of the folds has a distinct function: all-alpha-fold acts as a specificity determinant, directing RfaH to a small subset of operons, whereas the all-beta-fold recruits ribosome, thereby coupling RfaH-stimulated transcription to translation.
PMCID:3874879
PMID: 22817886
ISSN: 0092-8674
CID: 174083