HNPCC and MLH1

1. HNPCC and MLH1 Qi Peng Cancer Biology March 30th, 2006

2. Hereditary Nonpolyposis Colon Cancer (HNPCC) • An inherited cancer of digestive tract, especially increases risk of colon cancer. • Increases women’s risk of getting, endometrial and ovarian cancer • May also cause colon polyps.

3. Colorectal Cancer Facts • One of the most common cancers in the world. • In US alone, around 110,000 new cases every year.

4. HNPCC Facts • Responsible for 2% to 7% of all colorectal cancer. • Inherited in an autosomal dominant pattern. • Not all who inherit mutations will develop cancer .

5. Which Genes Went Wrong? • MLH1, MLH3, MSH2,MSH3,MSH6, and PMS2 • Repair DNA replication errors. • Mutations in any of these genes greatly increase DNA replication errors. • Mismatch Repair Pathway. • Members of mismatch repair (MMR) genes.

6. What Is MLH1 • MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli). • 3p21.3, between bp 37,009,982 to 37,067,340 on chromosome.

7. What is MLH1 • About 50% of HNPCC caused by MLH1 • a member of MMR genes • A tumor Suppressor • Hundreds of MLH1 mutations predispose people to colon cancer • prevent the production of MLH1 protein • Alter MLH1 protein, so it does not function properly.

8. Mismatch Repair Pathway

9. Mismatch Repair Pathway • Identify and eliminate base–base mismatches and insertion–deletion loops. • six different MMR proteins are required: MLH1, MLH3, MSH2, MSH3, MSH6, PMS2. • A sliding clamp model

10. Mismatch Repair Pathway

11. Mismatch Repair Pathway

12. MMP Sliding Clamp Model

13. MMR Protein

14. MLH1 and Mismatch Repair Pathway • MLH1 protein dimerizes with PMS2 to coordinate the interplay between the mismatch recognition complex and other proteins necessary for MMR.

15. What Went Wrong? MLH1 can be disrupted by: • missense mutations • truncating mutations • splice site mutations • large deletions • genomic rearrangements.

16. What Went Wrong • MLH1 acts in a recessive manner at the cellular level • Therefore, the 2-hit model stands. • Missense mutations do not eliminate the protein • Affect DNA binding • Affect protein- protein interactions.

17. If MLH1 Gene Does Not Work • DNA replication errors greatly increases and accumulates as cells continue to divide, which leads to • MMR Deficiency • Greater genomic instability • Eventually cancer.

18. MLH1 and Knock-out mice • show a replication error phenotype • Cells are deficient in MMR activity • Mutant males have no mature sperms • Mutant females are infertile

19. MLH1 and Knock-out mice

20. Bibliography • Bronner, C. E. et al. (1994) “Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer.” Nature,368, 258–261. • Buermeyer, A.B., Deschenes, S.M., Baker, S.M. and Liskay, R.M. (1999) Mammalian DNA mismatch repair. Annu. Rev. Genet., 33, 533–564. • Edelmann, Winfried et al . (1996) “Meiotic Pachytene Arrest in MLH1-Deficient Mice”. Cell, 85, 1125-1134. • Kolodner, R.D. and Marsischky, G.T. (1999) “Eukaryotic mismatch repair. “Curr. Opin. Genet. Dev., 9, 89–96 • Peltomäki, P. et al. (1993) “Genetic mapping of a locus predisposing to human colorectal cancer.” Science, 260, 810–812 • Peltomäki, P., Vasen, H.F.A. and the International Collaborative Group on HNPCC (1997) “Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study.” Gastroenterology, 113, 1146–1158. • Peltomäki, P. (2001) “Deficient DNA mismatch repair: a common etiologic factor for colon cancer.” Human Molecular Genetics, 10, 735-740.