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

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.

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

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.

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.

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.

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.

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

Mismatch Repair Pathway

MMP Sliding Clamp Model

MMR Protein

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.

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

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.

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.

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

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