450 East 29th Street
New York, NY 10016
http://nudlerlab.info/ Our laboratory pursues three major, not overlapping avenues:
1. Transcription Elongation and Gene Control. Transcription, the central step in gene expression and regulation, is carried out by DNA-dependent RNA polymerase (RNAP). Cellular RNAPs are large, multisubunit assemblies. Their complexity reflects an involvement in interactions with numerous regulatory signals and factors that modulate enzyme activity at all stages of transcription. Our research is focused on understanding of the transcription elongation process and its regulation at the detailed molecular level. Using various biochemical and protein chemical tools developed in the lab over the years, we address the following fundamental questions: how RNAP moves, how it responds to regulatory RNA and DNA signals and factors, and how it terminates transcription.
2. Natural RNA Sensors and Stress Response. Gene control systems in all organisms face a tremendous challenge to rapidly adjust gene expression to environmental changes. Traditionally, protein-based systems have been implicated in this process. However, we have discovered RNA transcripts that sense small molecules (metabolites) and stress directly to regulate a large number of genes in various organisms. One class of RNA sensors (a.k.a. riboswitches) monitors the level of metabolites (e.g. vitamins, amino acids, nucleotides) in bacteria, fungi, or plants via direct binding to those molecules. Riboswitches adjust gene expression to cellular needs by modulating transcription, translation, and RNA processing of cognate genes. We continue looking for new riboswitches and characterize mechanisms of known members of this group. Another type of an RNA sensor we found in eukaryotes from fly to man. This conserved non-coding RNA is essential for heat shock genes activation and is likely to monitor temperature. The exciting mechanism of this process is under investigation. Heat shock proteins (Hsp) are major cytoprotective components of the cell. They also play critical anti-apoptotic and anti-inflammatory roles. Many tumors display deregulated expression of Hsp, whose elevated levels contribute to resistance to chemo- and radiotherapy. Our long-term goal is the development of small molecules targeting the RNA thermosensor to treat cancer, ischemia/reperfusion injury, and inflammation.
3. Biochemistry and Physiology of Nitric Oxide. Nitric oxide (NO) is synthesized by arginine-oxidizing NO-synthases (NOS) in a wide variety of cells. Amazingly, this promiscuous free radical is involved in numerous biological functions, including vasodilation, blood clotting, neurotransmission, and inflammation. In many cases NO exerts its bioactivity by modifying (nitrosating and nitrating) proteins and small molecules. In the past several years we have uncovered a conceptually new mechanism explaining these reactions. Based on this mechanism, which relies on principals of micellar catalysis, we are designing low molecular weight compounds for manipulating NO bioactivity and treating various disorders associated with NO imbalance. In a separate line of research we study NO in bacteria and explore a possibility of using it as a new antimicrobial target. Analysis of bacterial genomes reveals that NOS exists in many Gram(+) bacteria including such notorious pathogens as S.aureus and B.anthracis. Our recent results demonstrate that NO protects bacteria from oxidative stress and suggest a possible role of NO in defending pathogens against immune oxidative attack.
S-nitrosylation of peroxiredoxin 1 contributes to viability of lung epithelial cells during Bacillus anthracis infection
Chung, Myung-Chul; Alem, Farhang; Hamer, Sarah G; Narayanan, Aarthi; Shatalin, Konstantin; Bailey, Charles; Nudler, Evgeny; Hakami, Ramin M. S-nitrosylation of peroxiredoxin 1 contributes to viability of lung epithelial cells during Bacillus anthracis infection. Biochimica & biophysica acta. 2016 Sep 7;1861(1 Pt A):3019-3029 (2238822)
En'Cas'ing the stress: Engineering a human cell line knockout of heat shock response coordinator genes using CRISPR Cas9 system
Isla-Inez, Canales G; Pani, B; Nudler, E. En'Cas'ing the stress: Engineering a human cell line knockout of heat shock response coordinator genes using CRISPR Cas9 system [Meeting Abstract]. FASEB journal. 2016 April 2016;30(no):- (2167582)
Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing
Jee, Justin; Rasouly, Aviram; Shamovsky, Ilya; Akivis, Yonatan; R Steinman, Susan; Mishra, Bud; Nudler, Evgeny. Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing. Nature. 2016 Jun 22;534(7609):693-696 (2159262)
ppGpp couples transcription to DNA repair in E. coli
Kamarthapu, Venu; Epshtein, Vitaly; Benjamin, Bradley; Proshkin, Sergey; Mironov, Alexander; Cashel, Michael; Nudler, Evgeny. ppGpp couples transcription to DNA repair in E. coli. Science. 2016 May;352(6288):993-996 (2112402)
Upregulation of cystathione beta-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury
Lechpammer, Mirna; Tran, Yen P; Wintermark, Pia; Martinez-Cerdeno, Veronica; Krishnan, Viswanathan V; Ahmed, Waseem; Berman, Robert F; Jensen, Frances E; Nudler, Evgeny; Zagzag, David. Upregulation of cystathione beta-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury. Brain pathology. 2016 Jul 28;:?-? (2191582)