Christopher Pearson , PhD
Genetics & Genome Biology
University of Toronto
Deptartment of Molecular Genetics
For more information, visit:
- Mechanisms of Genome Stability
- Trinucleotide Repeat Diseases
- DNA Replication, Repair and Mutation
- DNA Structure and Function
Mechanisms of Genome Stability and Trinucleotide Repeat Diseases
My research concerns the molecular mechanism(s) of genetic mutations involving trinucleotide repeat sequences. The mutation responsible for at least 21 serious human genetic diseases has been traced to the genetic variation in the lengths of specific trinucleotide repeats in DNA. Many of the diseases associated with this form of mutation affect the neurological or neuromuscular systems and include myotonic dystrophy (the most common form of muscular dystrophy), Huntington's disease, spinocerebellar ataxia types 1, 2, 3, 6 and 7, and fragile X (the most common form of inherited mental retardation).
Depending upon the disease gene the unstable repeats can be located in the 5'-UTR, the 3'-UTR, the intronic region, or the coding region (coding for glutamine residues). Repeat expansions can cause disease by altered transcription, altered transcript processing or an altered protein product. While the mode of disease may differ, common to each disease is the expansion mutation. To prevent or treat these diseases at the DNA level it is imperative to understand the molecular details of the mechanism of instability.
Our research focuses on the mechanisms and factors (cellular and genetic) that regulate the genetic instability of trinucleotide repeats. Mutations in tandemly repeated sequences may occur either during the process of DNA replication (genome duplication) or as a result of error-prone DNA repair or through DNA recombination. Strand slippage between direct repeats during replication can result in insertions or deletions of repeat units. My colleagues and I have demonstrated that trinucleotide repeats can easily form slipped strand DNA structures. The ability to form slipped structures is affected by both the length of the repeat tract as well as by the purity of the repeat tract-factors that are known to affect the genetic stability of the repeat tracts and disease in humans.
These correlation's provide strong evidence that slipped structures are mutagenic intermediates in the process of trinucleotide repeat expansion. Furthermore, we have shown that in addition to protein factors (such as DNA mismatch repair) genetic and epigenetic factors can contribute to the disease-associated repeat instability. Current research is aimed at 1) understanding the roles of human DNA replication and repair systems in trinucleotide instability; 2) understanding the formation and cellular processing of slipped strand DNA structures; and 3) repeat instability in various patient-derived cell lines.
Pearson, C.E. (2011) Repeat Associated Non-ATG Translation Initiation: One DNA, Two Transcripts, Seven Reading Frames, Potentially Nine Toxic Entities! PLoS Genetics, 7:e1002018.
TomÃ©, S., Panigrahi, G.B., LÃ³pez Castel, A., Foiry, L., Melton D.W., Gourdon G. & Pearson CE. (2011) Maternal germline-specific effect of DNA ligase I on CTG/CAG instability, Human Molecular Genetics, in press.
Seriola A, Spits C, Simard JP, Hilven P, Haentjens P, Pearson CE, Sermon K. (2011) Huntington's and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation, Human Molecular Genetics, 20:176-85.
López Castel A, Nakamori M, Tomé S, Chitayat D, Gourdon G, Thornton CA, Pearson CE. (2011) Expanded CTG repeat demarcates a boundary for abnormal CpG methylation in myotonic dystrophy patient tissues, Human Molecular Genetics, 20:1-15.
Nakamori M, Pearson CE & Thornton CA. (2011) Bidirectional transcription stimulates expansion and contraction of expanded (CTG)*(CAG) repeats, Human Molecular Genetics, 20:580-8.
Maternal germline-specific effect of DNA ligase I on CTG/CAG instability.TomÃ© S, Panigrahi GB, Castel AL, Foiry L, Melton DW, Gourdon G, Pearson CE. Hum Mol Genet. 2011 Mar 5.
Identification of restriction endonucleases sensitive to 5-cytosine methylation at non-CpG sites, including expanded (CAG)n/(CTG)n repeats. LÃ³pez Castel A, Nakamori M, Thornton CA, Pearson CE. Epigenetics. 2011 Apr 1;6(4).
Pearson CE. (2010) FSHD: a repeat contraction disease finally ready to expand (our understanding of its pathogenesis), PLoS Genetics, 6(10):e1001180.
Cleary JD, Tomé S, López Castel A, Panigrahi GB, Foiry L, Hagerman KA, Sroka H, Chitayat D, Gourdon G, Pearson CE. (2010) Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus, Nature Structure Molecular Biology, 17:1079-87.
Panigrahi GB, Slean MM, Simard JP, Gileadi O, Pearson CE. (2010) Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired, Proceedings of National Academy of Science USA, 107:12593-8.
López Castel A, Cleary JD, Pearson CE. (2010) Repeat instability as the basis for human diseases and as a potential target for therapy, Nature Review Molecular Cell Biology, 11:165-70.
Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats. Reddy K, Tam M, Bowater RP, Barber M, Tomlinson M, Nichol Edamura K, Wang YH, Pearson CE. Nucleic Acids Res. 2010 Nov 4.
Warby SC, Visscher H, Butland S, Pearson CE, Hayden MR. (2009) Response to Falush: a role for cis-element polymorphisms in HD, American Journal of Human Genetics, 85:942.
Tomé S, Holt I, Edelmann W, Morris GE, Munnich A, Pearson CE, Gourdon G. (2009) MSH2 ATPase domain mutation affects CTG*CAG repeat instability in transgenic mice, PLoS Genetics, 5(5):e1000482.
The ATTCT repeats of spinocerebellar ataxia type 10 display strong nucleosome assembly which is enhanced by repeat interruptions. Hagerman KA, Ruan H, Edamura KN, Matsuura T, Pearson CE, Wang YH. Gene. 2009 Apr 1;434(1-2):29-34.
López Castel A, Tomkinson A, Pearson CE. (2008) CTG/CAG repeat instability is modulated by LIGI-PCNA interaction and LIGI over expression: a distinction between replication and slipped-DNA repair, Journal Biological Chemistry, 284:26631-45.
Mutagenic roles of DNA "repair" proteins in antibody diversity and disease-associated trinucleotide repeat instability. Slean MM, Panigrahi GB, Ranum LP, Pearson CE. DNA Repair (Amst). 2008 Jul 1;7(7):1135-54.
CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, Axford MM, Cleary JD, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE, La Spada AR. PLoS Genet. 2008 Nov;4(11):e1000257.
Deletion hotspot in the argininosuccinate lyase gene: association with topoisomerase II and DNA polymerase alpha sites. Christodoulou J, Craig HJ, Walker DC, Weaving LS, Pearson CE, McInnes RR. Hum Mutat. 2006 Nov;27(11):1065-71.
Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier? Matsuura T, Fang P, Pearson CE, Jayakar P, Ashizawa T, Roa BB, Nelson DL. Am J Hum Genet. 2006 Jan;78(1):125-9.
Repeat instability: mechanisms of dynamic mutations. Pearson CE, Nichol Edamura K, Cleary JD. Nat Rev Genet. 2005 Oct;6(10):729-42.
DNA methylation and replication: implications for the "deletion hotspot" region of FMR1. Nichol Edamura K, Pearson CE. Hum Genet. 2005 Nov;118(2):301-4.
Edamura KN, Leonard MR, Pearson CE. (2005) Role of replication and CpG methylation in fragile X syndrome CGG deletions in primate cells. American Journal of Human Genetics, 76:302-311 (News & Views, American Journal of Human Genetics, 76:i-ii)
Mulvihill DJ, Edamura KN, Hagerman KA, Pearson CE, Wang YH. (2004) Effect of CAT or AGG interruptions and CpG methylation on nucleosome assembly upon trinucleotide repeats of spinocerebellar ataxia type 1 and fragile X syndrome, Journal of Biological Chemistry, 280:4498-4503
Pearson CE. (2003) Slipping while sleeping? trinucleotide expansions in germ cells. Trends in Molecular Medicine, 11:483-488
Yang Z, Lau R, Marcadier J, Chitayat D, Pearson CE. (2003) Replication inhibitors modulate the instability of an expanded trinucleotide repeat at the DM1 locus in human cells. American Journal of Human Genetics, 73:1092-1105.
Tam M, Montgomery SE, Kekis M, Stollar BD, Price GB, Pearson CE. (2003) Slipped (CTG)(CAG) repeats of the myotonic dystrophy locus: Surface-probing with anti-DNA antibodies. Journal of Molecular Biology, 332:585-600.
Marcadier JL, Pearson CE. (2003) Fidelity of primate cell repair of a double-strand break in a (CTG)(CAG) tract: Effect of structure. Journal of Biological Chemistry, 278:33848-33856.
Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC, Moses K, Warren ST. (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron, 39:739-747.
Cleary JD, Pearson CE. (2003) The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenetics & Genome Research, 100:25-55. (cover photo).
Libby RT, Monckton DG, Fu Y.-H, Martinez RA, McAbney JP, Lau R, Einum DD, Nichol K, Ware CB, Ptacek LJ, Pearson CE, LaSpada AR. (2003) Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice, Human Molecular Genetics, 12:41-50.
Pearson, C.E., Tam, M., Wang, Y.-H., Montgomery, S.E., Dar, A.C., Cleary, J.D., Nichol, K. (2002) Slipped-strand DNAs formed by long (CAG)*(CTG) repeats: slipped-out repeats and slip-out junctions, Nucleic Acids Research, 30:4534-47.
Nichol, K., Pearson, C.E. (2002) CpG methylation modifies the genetic stability of cloned repeat sequences, Genome Research, 12:1246-56.
Cleary, J.D., Nichol, K., Wang, Y.-H., Pearson, C.E. (2002) Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells, Nature Genetics, 31:37-46.
Sinden, R.R., Potaman, V.N., Oussatcheva, E.A., Pearson, C.E., Lyubchenko, Y.L., Shlyakhtenko, L.S. (2002) Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA, Journal of Bioscience, 27(1 Suppl 1):53-65.
Panigrahi, G.B., Cleary, J.D., Pearson, C.E. (2002) In vitro (CTG)*(CAG) expansions and deletions by human cell extracts, Journal of Biological Chemistry, 277:13926-34.
Novac, O., Alvarez, D., Pearson, C.E., Price, G.B., Zannis-Hadjopoulos, M. (2002) The human cruciform-binding protein, CBP, is involved in DNA replication and associates in vivo with mammalian replication origins, Journal of Biological Chemistry, 277:11174-83.
LeProust, E.M., Pearson, C.E., Sinden, R.R., Gao, X. (2000) Unexpected formation of parallel duplex in GAA and TTC trinucleotide repeats of Friedreich's ataxia, ,Journal of Molecular Biology, 302:1063-80.
Westwood, N.B., Gruszka-Westwood, A.M., Pearson, C.E., Delord, C.F., Green, A.R., Huntly, B.J., Lakhani, A., McMullin, M.F., Pearson, T.C. (2000) The incidences of trisomy 8, trisomy 9 and D20S108 deletion in polycythaemia vera: an analysis of blood granulocytes using interphase fluorescence in situ hybridization.
A detailed list of Dr. Pearson's publications can be found on PubMed.