MLH1 andHereditary 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 • 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.
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.