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MLH1 and Hereditary Non-Polyposis Colorectal Cancer. An investigation of DNA mismatch repair By: Daniel Driskill March 22, 2007. HNPCC. Aka: Lynch Syndrome Susceptibility to: Endometrial, stomach, ovarian, and urinary tract, and colon carcinomas Very specific criteria for diagnosis

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mlh1 and hereditary non polyposis colorectal cancer

MLH1 andHereditary Non-Polyposis Colorectal Cancer

An investigation of DNA mismatch repair

By: Daniel Driskill

March 22, 2007

hnpcc
HNPCC
  • Aka: Lynch Syndrome
  • Susceptibility to:
    • Endometrial, stomach, ovarian, and urinary tract, and colon carcinomas
  • Very specific criteria for diagnosis
  • High Penetrance
  • Early Onset
  • 80% lifetime risk of developing CRC.
genes involved
Genes Involved
  • MLH1 and MSH2 mutated in germline
  • These are Mismatch Repair genes…
    • Repair post-replication errors made by polymerase
    • Involved in double-strand excision and recombination of DNA strands
  • Functional gene product:

MLH1 + PMS2

genes involved1
Genes Involved

Chen et. al. (2005) Cancer Res. 65, 8662-8670

inherited cancer
Inherited Cancer
  • Autosomal Dominant
    • but…shown that genes loose their function???
  • Cells experience loss of heterozygosity
  • Null mutations in mice leads to sterility!
mlh1 can be mutated
MLH1 Can be Mutated
  • 2 ways:
    • Germline mutations
      • Truncation of protein
    • Hypermethylation of Promotor
      • Dampens expression
mismatch repair in e coli
Mismatch Repair in E. coli
  • Involvement in MMR pathway
  • Methyl-directed MM repair
  • Key players:
    • MutH – site specific (GATC) endonuclease.
    • MutS recognizes MM, interacts with MutL
    • MutL interacts and modulates the activities of many proteins

Robertson, et. al. (2006) J. Biol. Chem. 281, 19949–19959.

bacteria vs mammals
Bacteria vs. Mammals
  • No methyl-directed MMR in Mammals.
  • No known mechanism for recognizing good strand.
  • No MutH homologue in Mammals.
microsatellite instability
Microsatellite Instability

Inability to properly detect and repair sequence mismatches leads to

high rates of mutations

in microsatellite repeat regions.

credits
Credits
  • Chen, P.C., S. Dudley, W. Hagen, D. Dizon, L. Paxton, D. Reichow, S.R. Yoon, K. Yang, N. Arnheim, R. M. Liskay, and S. M. Lipkin. (2005) Cancer Res. 65, 8662-8670.
  • Jacob, S. and F. Praz. (2002) Biochimie. 84, 27-47.
  • Peltomaki, P. (2001) Human Mol Gen. 10, 735-740.
  • Robertson, A.B., S. R. Pattishall, E. A. Gibbons, S. W. Matson. (2006) J. Biol. Chem. 281, 19949–19959.
  • Weinberg, R.
  • Yao, X., A. B. Buermeyer, L. Narayanan, D. Tran, S. M. Baker, T. A. Prolla, P. M. Glazer, R. M. Liskay, and n. Arnheim. (1999) Proc. Natl. Acad. Sci. 96, 6850-6855.