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 is a major DNA repair system that protects humans from both sporadic and inherited cancers. 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, participates in DNA damage response, 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 ~100 fold and strongly predisposes the affected individuals to both inherited and sporadic cancers. Loss-of-function 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), 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 human DNA mismatch repair. Several human DNA mismatch repair reactions have been reconstituted with purified proteins and defined DNA substrates. The key human 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. This DNA mismatch repair reaction is initiated as a result of mismatch recognition by MutSα. After recognizing the mismatch, MutSα cooperates with loaded PCNA to activate MutLα endonuclease. The activated MutLα endonuclease incises the discontinuous daughter strand 5' and 3' to the mismatch. An incision produced by MutLα  5' to the mismatch is utilized by MutSα-activated EXO1 to enter the DNA and remove the mismatch in a 5'→3' excision reaction modulated by RPA. The generated gap is repaired by the Pol δ holoenzyme.

EXO1 is the only exonuclease that has been implicated in human DNA mismatch repair. Studies in the yeast, mouse, and human systems indicate that DNA mismatch repair remains active in the absence of EXO1. Consistent with this, EXO1-independent mismatch repair reaction has been reconstituted in a defined system. In an early step of this reaction, the activated MutLα endonuclease incises the discontinuous daughter strand. Then a 3' DNA end generated by the activated MutLα endonuclease 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 operates in the chromatin environmentt.

Recent Publications

Dahal, B.K., Kadyrova, L.Y., Delfino, K.R., Rogozin, I.B., Gujar, V., Lobachev, K.S., and F.A. Kadyrov. 2017. Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae. PLOS Genetics, 13(10), e1007074.

Genschel, J., Kadyrova, L.Y., Iyer, R.R., Dahal, B.K., Kadyrov, F.A., and P. Modrich. 2017. Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair. Proc. Natl. Acad. U.S.A.114:4930-4935.

Kadyrova, L.Y., B.K. Dahal, and F.A. Kadyrov. 2016. 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. 291:27298-27312.

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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