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Mikhail  Kashlev, Ph.D.

Mikhail Kashlev, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
RNA Biology Laboratory

RESEARCH SUMMARY

Dr. Kashlev investigates the mechanisms regulating transcription elongation by Escherichia coli (E. coli) RNA polymerase and the yeast RNA polymerase II (Pol II). He is strongly convinced that the single cell organisms (E. coli and the budding yeast) will continue to be most instrumental in understanding the basic principles of induced and spontaneous mutagenesis of DNA, which lead to tumorogenesis. Dr. Kashlev and his team investigate the following subjects: (1) mechanism of transcription-coupled DNA damage repair, (2) mechanisms employed by Pol II for transcription across bulky DNA lesions such as pyrimidine dimers and cyclopurines, and (3) mechanisms regulating transcriptional fidelity.

Areas of Expertise

1) mutagenesis of DNA, 2) transcriptional fidelity, 3) Pol II

Publications

Selected Recent Publications

NusG-Dependent RNA Polymerase Pausing and Tylosin-Dependent Ribosome Stalling Are Required for Tylosin Resistance by Inducing 23S rRNA Methylation in Bacillus subtilis

Yakhnin H, Yakhnin AV, Mouery BL, Mandell ZF, Karbasiafshar C, Kashlev M, Babitzke P.
mBio. 10(6): e02665-19, 2019. [ Journal Article ]

RNA-DNA and DNA-DNA base-pairing at the upstream edge of the transcription bubble regulate translocation of RNA polymerase and transcription rate

KIreeva M, Trang C, Matevosyan G, Turek-Herman J, Chasov V, Lubkowska L, Kashlev M.
Nucleic Acids Res. 46(11): 5764-75, 2018. [ Journal Article ]

Structural basis of transcriptional stalling and bypass of abasic DNA lesion by RNA polymerase II

Wang W, Walmacq C, Chong J, Kashlev M, Wang D.
Proc Natl Acad Sci U S A. 115(11): E2538-E2545, 2015. [ Journal Article ]

A Cre Transcription Fidelity Reporter Identifies GreA as a Major RNA Proofreading Factor in Escherichia coli

Bubunenko MG, Court CB, Rattray AJ, Gotte DR, Kireeva ML, Irizarry-Caro JA, Li X, Jin DJ, Court DL, Strathern JN, Kashlev M.
Genetics. 206(1): 179-187, 2017. [ Journal Article ]

Visualizing translocation dynamics and nascent transcript errors in paused RNA polymerases in vivo

Imashimizu M, Takahashi H, Oshima T, McIntosh C, Bubunenko M, Court DL, Kashlev M
Genome Biology. 16(1): 98, 2015. [ Journal Article ]

Job Vacancies

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Team

Postbaccalaurate Fellow (CRTA)
Luke Berger
Visiting Scientist (Contr.)
Mikhail Bubunenko , Ph.D.
Senior Research Assistant
Lucyna Lubkowska, Ph.D.
Postdoctoral Fellow (Visiting)
Smriti Singh, Ph.D.
Special Volunteer
Gokhan Tolun, Ph.D.
Staff Scientist
Alexander Yakhnin, Ph.D.

Covers

cover of Chemical Reviews Nov 2013

RNA Polymerase Structure, Function, Regulation, Dynamics, Fidelity, and Roles in GENE EXPRESSION

Published Date

Multi-subunit RNA polymerases (RNAP) are ornate molecular machines that translocate on a DNA template as they generate a complementary RNA chain. RNAPs are highly conserved in evolution among eukarya, eubacteria, archaea, and some viruses. As such, multi-subunit RNAPs appear to be an irreplaceable advance in the evolution of complex life on earth. Because of their stepwise movement on DNA, RNAPs are considered to be molecular motors, and because RNAPs catalyze a templated polymerization reaction, they are central to biological information flow. The history of RNAP discovery and investigation of its mechanism and regulation appear as complex as RNAP itself. The central role of templated RNA synthesis in biological information flow was predicted by Jacob and Monod, and the enzymatic activity promoting formation of RNA polymers was reported in eubacteria and eukaryotes at that time by several groups. However, the DNA-dependent RNA polymerase proved elusive until 1960, when it was independently identified in bacteria by Hurwitz and Stevens and in plants by the Bonner group.

Citation

M. Kireeva, M. Kashlev, Z. Burton Chem. Rev., 2013, 113 (11), pp 8325–8330

Cover of Molecular Cell April 1, 2005

Nature of the Nucleosomal Barrier to RNA Polymerase II

Published Date

In the cell, RNA polymerase II (pol II) efficiently transcribes DNA packaged into nucleosomes, but in vitro encounters with the nucleosomes induce catalytic inactivation (arrest) of the pol II core enzyme. To determine potential mechanisms making nucleosomes transparent to transcription in vivo, we analyzed the nature of the nucleosome-induced arrest. We found that the arrests have been detected mostly at positions of strong intrinsic pause sites of DNA. The transient pausing makes pol II vulnerable to arrest, which involves backtracking of the elongation complex for a considerable distance on DNA. The histone-DNA contacts reestablished in front of pol II stabilize backtracked conformation of the polymerase. In agreement with this mechanism, blocking of backtracking prevents nucleosome-induced arrest. Transcript cleavage factor TFIIS reactivates the backtracked complexes and promotes pol II transcription through the nucleosome. Our findings establish the crucial role of elongation factors that suppress pol II pausing and backtracking for transcription in the context of chromatin.

Citation

Maria Kireeva, Brynne Hancock, Gina Cremona, WendyWalter, Vasily Studitsky, Mikhail Kashlev, Molecular Cell, Vol. 18, 97-108, April 1, 2005