Farid Kadyrov received his PhD in Biochemistry in 1997 from the Institute of Biochemistry and Physiology of Microorganisms of the Russian Academy of Sciences at Pushchino. After completing postdoctoral trainings with Jan Drake at NIEHS and Paul Modrich at Duke University, he joined the SIUC faculty in 2008. Farid Kadyrov has a joint appointment with the Department of Biochemistry and Molecular Biology and the SimmonsCooper Cancer Institute.
(618) 453-6405
email: fkadyrov@siumed.edu
Research in my laboratory is focused on understanding molecular mechanisms and protein factors responsible for DNA repair and genetic stability in human cells. Extra- and intra-cellular insults and DNA replication errors constantly introduce chemical modifications into the DNA structure. These chemical changes, if left un-repaired, give rise to mutations that have a strong potential to trigger carcinogenesis as well as development of other genetic diseases. Living cells contain highly sophisticated DNA repair machineries that counteract DNA damage by reversing unwanted chemical changes of DNA. Several major DNA repair pathways have been described and include base excision repair, direct damage reversal, mismatch repair, nucleotide excision repair, non-homologous end joining, repair by means of homologous recombination, and repair of inter-strand crosslinks.
We are currently interested in human mismatch repair. The major function of mismatch repair is the correction of DNA replication errors. Mismatch repair also corrects DNA mismatches formed during homologous recombination, suppresses recombination between semi-homologous DNA sequences, initiates cell signaling and apoptotic response to DNA damage of several classes, and is required for generation of immunoglobulin diversity. Inactivation of mismatch repair increases spontaneous mutation rates 10-1000 fold and strongly predisposes to carcinogenesis. Mutations in mismatch repair genes MLH1, PMS2, MSH2, and MSH6 are responsible for about 15% of sporadic cancers in several different tissues and are the basis of a major inherited cancer syndrome (hereditary nonpolyposis colorectal cancer (HNPCC)). Mismatch repair deficiency has been also linked to Turcot syndrome, a childhood condition characterized by a primary brain tumor associated with multiple colorectal adenomas.
Mechanistic steps of human biochemical pathway responsible for the correction of DNA replication errors are quite well understood, and a minimal system capable of bidirectional removal of base-base mismatches has been reconstituted using purified proteins and defined DNA substrates (see inset figure). A key step in this pathway is incision of mismatch-containing DNA by MutL(alpha) endonuclease (MLH1-PMS2 heterodimer). The endonuclease activity of MutL(alpha) requires the presence of the mismatch recognition factor MutS(alpha), a DNA mismatch, the PCNA clamp, the RFC clamp loader, ATP, and a pre-existing strand break. Incisions introduced by MutL(alpha) endonuclease serve as entry sites for MutS(alpha)-activated Exonuclease I to excise the mismatch in a 5'-3' reaction. The generated gap is removed by the action of DNA polymerase delta holoenzyme.
There are many unanswered questions in the mismatch repair field. We are currently
focused on understanding how different enzymatic activities of human MutL homologs
contribute to mismatch repair, genetic recombination, and cancer suppression.
Liu, Y., F.A. Kadyrov, and P. Modrich. 2011. PARP-1 enhances the mismatch-dependence of 5'-directed excision in human mismatch repair in vitro. DNA Repair, 10(11):1145-53.
Kadyrova, L.Y., E. Rodriges Blanko, & F.A. Kadyrov. 2011. CAF-I-dependent control of degradation of discontinuous strands during mismatch repair. Proc. Natl. Acad. U.S.A., 108(7):2753-8.
Pluciennik, A., L. Dzantiev, R.R. Iyer, N. Constantin, F.A. Kadyrov, and P. Modrich. 2010. PCNA function in activation and strand-direction of MutL(alpha) endonuclease in mismatch repair. Proc. Natl. Acad. U.S.A. 107:16066-16071.
Kadyrov, F.A., J. Genschel, Y. Fang, E. Penland, W. Edelman, and P. Modrich. 2009. A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair. Proc. Natl. Acad. U.S.A. 106:8495-8500.
Kadyrov, F. A., A. E. Mercedes, S. F. Holmes, O. Lukianova, M. O’Donnell, T. A. Kunkel, and P. Modrich. 2007. Saccharomyces cerevisiae MutL(alpha) is a mismatch repair endonuclease. J. Biol. Chem. 282:37181-37190.
Kadyrov, F. A., L. Dzantiev, N. Constantin, and P. Modrich. 2006. Endonucleolytic function of MutL(alpha) in human mismatch repair. Cell 126:297-308.
Constantin, N., L. Dzantiev, F. A. Kadyrov, and P. Modrich. 2005. Human mismatch repair: reconstitution of a nick-directed bidirectional reaction. J. Biol. Chem. 280:39752-39761.
Kadyrov, F. A., and J. W. Drake. 2004. UvsX recombinase and Dda helicase rescue stalled bacteriophage T4 DNA replication forks in vitro. J. Biol. Chem. 279:35735-35740.
Kadyrov, F. A., and J. W. Drake. 2003. Properties of bacteriophage T4 proteins deficient in replication repair. J. Biol. Chem. 278:25247-25255.
Kadyrov, F. A., and J. W. Drake. 2002. Characterization of DNA synthesis catalyzed by bacteriophage T4 replication complexes reconstituted on synthetic circular substrates. Nucl. Acids Res. 30:4387-4397.
Kadyrov, F. A., M. G. Shlyapnilov, and V. M. Kryukov. 1997. A bacteriophage T4 site-specific endonuclease, SegE, is responsible for a non-reciprocal genetic exchange between T-even-related phages. FEBS Lett. 415:75-80.
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