mlh1 and hereditary non-polyposis colorectal cancer
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
MLH1 and
Hereditary Non-Polyposis Colorectal Cancer
An investigation of DNA mismatch repairBy: Daniel DriskillMarch 22, 2007
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
• 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 Involved
Chen et. al. (2005) Cancer Res. 65, 8662-8670
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
• 2 ways:
– Germline mutations• Truncation of protein
– Hypermethylation of Promotor• Dampens expression
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
• No methyl-directed MMR in Mammals.
• No known mechanism for recognizing good strand.
• No MutH homologue in Mammals.
Microsatellite Instability
Inability to properly detect and repair sequence mismatches leads to
high rates of mutations
in microsatellite repeat regions.
Questions…
?
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.