1 / 12

MLH1 and Hereditary Non-Polyposis Colorectal Cancer

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

alexis-chen
Download Presentation

MLH1 and Hereditary Non-Polyposis Colorectal Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. MLH1 andHereditary Non-Polyposis Colorectal Cancer An investigation of DNA mismatch repair By: Daniel Driskill March 22, 2007

  2. 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.

  3. 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

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

  5. Inherited Cancer • Autosomal Dominant • but…shown that genes loose their function??? • Cells experience loss of heterozygosity • Null mutations in mice leads to sterility!

  6. MLH1 Can be Mutated • 2 ways: • Germline mutations • Truncation of protein • Hypermethylation of Promotor • Dampens expression

  7. 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.

  8. Bacteria vs. Mammals • No methyl-directed MMR in Mammals. • No known mechanism for recognizing good strand. • No MutH homologue in Mammals.

  9. Microsatellite Instability Inability to properly detect and repair sequence mismatches leads to high rates of mutations in microsatellite repeat regions.

  10. Questions… ?

  11. 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.

More Related