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MLH1 and Hereditary Non-polyposis Colon Cancer

MLH1 and Hereditary Non-polyposis Colon Cancer

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MLH1 and Hereditary Non-polyposis Colon Cancer

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  1. MLH1and Hereditary Non-polyposis Colon Cancer Walter Ratchford 3/4/04

  2. Outline • Explanation of MMR in DNA replication • Description of MLH1 and its role in MMR • The link between hereditary non-polyposis colon cancer and MLH1

  3. DNA Mismatch Repair (MMR) • Correction of mismatched nucleotides and small insertion-deletion loops • DNA replication errors thought to be 1/1000 nucleotides. Over 99.9% corrected by MMR • Studied primarily in E.coli • Involves three proteins MutS, MutL, and MutH in E. Coli

  4. DNA MMR Single base pair mismatch

  5. DNA MMR • Typically affect repetitive sections of DNA • Gain or loss of short repeated units • Capable of repairing 1,2, and 3 extra nucleotide loops • Caused by the slippage of DNA during replication Mechanism of insertion-deletion loops

  6. DNA MMR in E. Coli MutS/MutL complex activates MutH which locates a nearby methyl group, and nicks the newly synthesized DNA MutS recognizes mismatched DNA MutL acts as stabilizer for MutS/DNA interaction Excision is accomplished by cooperation between the UvrD (Helicase II) protein, which unwinds from the nick in the direction of the mismatch, and a single-strand specific exonuclease of appropriate polarity, followed by resynthesis and ligation by DNA ligase. http://saturn.roswellpark.org/cmb/huberman/DNA_Repair/mmr.html

  7. DNA MMR in Humans

  8. DNA MMR in Humans http://www.imr.unizh.ch/research/marra/HNPCC/hnpcc.html#

  9. MutL homolog 1 (MLH1) • Human homolog of MutL in E. Coli • Located on Chromosome 3p • Encodes a 756 amino acid protein • 19 exons • Involved in the correction of base-base mismatches and insertion-deletion loops from errors induced during DNA replication and recombination http://www.utoronto.ca/LabMedPathobiology/education/undergraduate/365/2004lecture%20notes/Elsholtz365-3(2004)_copy.pdf

  10. MLH1 Crystal Structure of 40 Kd segment of protein www.rcsb.org

  11. MLH1 and hereditary non-polyposis colon cancer (HNPCC) • Defined as inactivating germline mutations in genes encoding • MMR proteins • No MLH1 = cancer predisposition....tumor formation • Autosomal dominant inheritance • Recessive cancer phenotype A benign neoplastic polyp - Adenoma http://www.imr.unizh.ch/research/marra/HNPCC/hnpcc.html

  12. HNPCC Inheritance http://www.imr.unizh.ch/research/marra/HNPCC/hnpcc.html • Inherited mutation in one of the MMR genes • Subsequent loss of heterozygosity (Two Hit • Hypothesis) • 20% of sporadic colorectal cancers due to MMR • gene mutations

  13. Accounts for 3% of colon cancers • Tumors also develop in urinary tract, stomach, ovary, small • bowel, and endometrium • 85% penetrance • 70% HNPCC patients have mutation in MLH1 or MSH2 HNPCC