Farid Kadyrov

Associate Professor

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 John Drake at NIEHS and Paul Modrich at Duke University, he joined the SIUC faculty in 2008.

(618) 453-6405
email: fkadyrov@siumed.edu

 

The DNA mismatch repair system in genetic stability and cancer suppression

The DNA mismatch system has been conserved in the majority of living organisms. The primary function of the DNA mismatch repair system is the correction of DNA replication errors.  It also removes DNA mismatches formed during homologous recombination, suppresses homeologous recombination, initiates apoptosis in response to DNA damage of several classes, and contributes to the somatic hypermutagenesis and class switch recombination stages of the immune response. Inactivation of the DNA mismatch repair system increases the spontaneous mutation rate ~30-1000 fold and strongly predisposes the affected individuals to both inherited and sporadic cancers. Deleterious mutations in the DNA mismatch repair system genes MLH1, PMS2, MSH2, and MSH6 are the molecular basis of two cancer predisposition syndromes: Lynch syndrome and Turcot syndrome. Furthermore, it is known that methylation of the MLH1 promoter is responsible for about 15% of sporadic cancers in a number of different tissues.

Current evidence indicates that the primary mismatch recognition factor MutSα (MSH2-MSH6 heterodimer), MutLα endonuclease (MLH1-PMS2 heterodimer in humans and Mlh1-Pms1 heterodimer in budding yeast), the replicative clamp PCNA, the clamp loader RFC, the 5'→3' exonuclease EXO1, the secondary mismatch recognition factor MutSβ (MSH2-MSH3 heterodimer), and DNA polymerase δ (Pol δ) are required for postreplicative DNA mismatch repair. Several eukaryotic DNA mismatch repair reactions have been reconstituted with purified proteins and defined DNA substrates. The key eukaryotic reaction that has been reconstituted depends on the activities of the primary mismatch recognition factor MutSα,  MutLα endonuclease, the PCNA clamp, the clamp loader RFC, EXO1, the ssDNA-binding protein RPA, and Pol δ. In this reaction, MutSα recognizes the mismatch and then cooperates with loaded PCNA to activate MutLa endonuclease. The activated MutLα endonuclease can incise the discontinuous strand 5' and 3' to the mismatch. An incision produced by MutLα  5' to the mismatch is utilized by EXO1 to enter the DNA and excise a segment of the discontinuous strand encompassing the mismatch in a 5'→3' reaction modulated by RPA. The generated gap is repaired by the Pol δ holoenzyme. EXO1 is the only exonuclease that has been implicated in postreplicative DNA mismatch repair. Studies in the yeast, mouse and human systems indicate that postreplicative MMR can occur in the absence of EXO1. Consistent with this, EXO1-independent mismatch repair reaction has been reconstituted. The initial steps in EXO1-independent mismatch repair reaction that lead to the incision of the discontinuous strand by activated MutLα endonuclease are the same as those in EXO1-dependent mismatch repair reaction. Then a 3' DNA end generated by activated MutLα 5' to the mismatch is extended by the Pol δ holoenzyme in a strand displacement DNA synthesis reaction that removes the mismatch.

There are many unanswered questions in the field. We are currently focused on understanding how the DNA mismatch repair system acts in and cooperates with the nucleosomal environment.

Recent Publications

Kadyrova, L.Y., B.K. Dahal, and F.A. Kadyrov. 2017. The major replicative histone chaperone CAF-1 suppresses the activity of the DNA mismatch repair system in the cytotoxic response to a DNA methylating agent. J. Biol. Chem. (in press).

Rodriges Blanko, E., Kadyrova, L.Y., and F.A. Kadyrov. 2016. DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition. J. Biol. Chem. 291:9203-9217.

Kadyrova, L.Y., and F.A. Kadyrov. 2016. Endonuclease activities of MutLα and its homologs in DNA mismatch repair. DNA Repair. 38:42-49.

Kadyrova, L.Y., B.K. Dahal, and F.A. Kadyrov. 2015. Evidence that the DNA mismatch repair system removes 1-nucleotide Okazaki fragment flaps. J. Biol. Chem. 290:24051-24065.

Kadyrova, L.Y., T.M. Mertz, Y. Zhang, M.R. Northam, Z. Sheng, K.S. Lobachev, P.V. Shcherbakova, and F.A. Kadyrov. 2013. A reversible histone H3 acetylation cooperates with mismatch repair and replicative polymerases in suppressing genome instability. PLOS Genetics, 9:1-16, e1003899.

Kadyrova, L.Y., E. Rodriges Blanko, and F.A. Kadyrov. 2013. Human CAF-1 dependent nucleosome assembly in a defined system. Cell Cycle. 12:3286-3297.

Schorf, B., S. Bregenhorn, J. Quivy, F.A. Kadyrov, G. Almouzni, and J. Jiricny, J. 2012. Interplay between mismatch repair and chromatin assembly. Proc. Natl. Acad. U.S.A. 109:1895-900.

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 MutLα 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.

Brok-Volchanskaya, V.S., F.A. Kadyrov, D.E. Sivogrivov, P.M. Kolosov, A.S. Sokolov, M.G. Shlyapnikov, V.M. Kryukov, and I. E. Granovsky. 2008. Phage T4 SegB protein is a homing endonuclease required for the preferred inheritance of T4 tRNA region occurring in co-infection with a related phage. Nucl. Acids Res. 36:2094-2105.

Kadyrov, F. A., A. E. Mercedes, S. F. Holmes, O. Lukianova, M. O’Donnell, T. A. Kunkel, and P. Modrich. 2007. Saccharomyces cerevisiae MutLα 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 MutLα 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.

 

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