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MSH2 (MutS homolog, hereditary non-polyposis colon cancer)

MSH2 (MutS homolog, hereditary non-polyposis colon cancer). By Katie Butler. To determine function of MSH2 we study MutS in E. Coli. Why? Pathway better understood Pathway highly conserved in humans. Role of MutS. Mismatch Repair Machinery. DNA Damage.

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MSH2 (MutS homolog, hereditary non-polyposis colon cancer)

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  1. MSH2(MutS homolog, hereditary non-polyposis colon cancer) By Katie Butler

  2. To determine function of MSH2 we study MutS in E. Coli • Why? • Pathway better understood • Pathway highly conserved in humans

  3. Role of MutS • Mismatch Repair Machinery

  4. DNA Damage • DNA damage occurs frequently in the cell • Different repair mechanisms http://www.gurdon.cam.ac.uk/~jacksonlab/m7_spj_2006/lecture_1.pdf

  5. DNA Polymerase Slippage(Microsatellite Instability) www.stanford.edu

  6. Mismatch Repair in E. Coli(Initiation, Excision, Resynthesis) http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/muth/molmast.htm

  7. How does this compare to Eukaryotes? • Highly conserved • More complex • Strand recognition

  8. MSH2 in Eukaryotes http://hmg.oxfordjournals.org/content/vol10/issue7/images/large/dde07501.jpeg

  9. What happens when MSH2 is mutated? What is the role of MSH2 in cancer? • We will begin by looking at the Mouse Model!

  10. MSH2 (-/-) Viable lymphoma cancers ~ 2 months Mutator phenotype Microsatellite instability MSH2 (+/-) lymphomas around ~ 8 months Knudson’s 2 hit theory Mouse Model

  11. What happens when MSH2 is mutated in humans? • Hereditary Non-polyposis Colon Cancer

  12. What is Hereditary non-polyposis Colin Cancer? • The name is deceiving • Most common form of hereditary colon cancer • Occurs when any of the genes involved in Mismatch Repair are mutated • MSH2 the focus for today

  13. HereditaryNon-Polyposis Colon Cancer • Autosomal Dominance Inheritance • Highly Penetrate 80% Example of Family effected by HNPCC

  14. Pathway to Cancer http://www.jewishgeneticscenter.org/images/fig2.gif

  15. Questions?!

  16. References • Jacob, S., & Praz, F. (2002). DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie, 82, 27-47. • Maguire, K. K., & Kmiec, E. B. (2007). Multiple roles for MSH2 in the repair of a deletion mutation directed by modified single-stranded oligonucleotides [Electronic version]. Gene, 386, 107-114. • Acharya, S., Foster, P.L., Brooks, P., & Fishel, R. (2003). The Coordinated Functions of the E. coli MutS and MutL Proteins in Mismatch Repair [Electronic version]. Molecular Cell, 12, 233-246. • Burr, K, Duyn-Goedhart, A., Hickenbotham, P, Monger, K., Buul P.W.,& Dubrova, Y.E. (2007) The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline. [Electronic version]. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 617, 147-151.

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