MLH1 and Hereditary Non-Polyposis Colorectal Cancer

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.