Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs

Guo Min Li, Paul Modrich

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337 Citations (Scopus)

Abstract

Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the hMLHI gene. We have purified to near homogeneity an activity from HeLa cells that complements H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the eight base-base mismatches as well as a number of slipped- strand, insertion/deletion mispairs. This activity behaves as a single species during fractionation and copurifies with proteins of 85 and 110 kDa. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the hMLHI product and the latter to the product of hPMS2 or a closely related gene. The 1:1 molar stoichiometry of the two polypeptides and their hydrodynamic behavior indicate formation of a heterodimer, which we have designated hMutLα. These observations indicate that interactions between members of the family of human MutL homologs may be restricted.

Original languageEnglish (US)
Pages (from-to)1950-1954
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number6
DOIs
StatePublished - Mar 14 1995

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DNA Mismatch Repair
Colorectal Neoplasms
Nucleic Acid Heteroduplexes
Hydrodynamics
HeLa Cells
Genes
Proteins
Alleles
Peptides
MutL Proteins

Keywords

  • cancer
  • genetic instability

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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abstract = "Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the hMLHI gene. We have purified to near homogeneity an activity from HeLa cells that complements H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the eight base-base mismatches as well as a number of slipped- strand, insertion/deletion mispairs. This activity behaves as a single species during fractionation and copurifies with proteins of 85 and 110 kDa. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the hMLHI product and the latter to the product of hPMS2 or a closely related gene. The 1:1 molar stoichiometry of the two polypeptides and their hydrodynamic behavior indicate formation of a heterodimer, which we have designated hMutLα. These observations indicate that interactions between members of the family of human MutL homologs may be restricted.",
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N2 - Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the hMLHI gene. We have purified to near homogeneity an activity from HeLa cells that complements H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the eight base-base mismatches as well as a number of slipped- strand, insertion/deletion mispairs. This activity behaves as a single species during fractionation and copurifies with proteins of 85 and 110 kDa. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the hMLHI product and the latter to the product of hPMS2 or a closely related gene. The 1:1 molar stoichiometry of the two polypeptides and their hydrodynamic behavior indicate formation of a heterodimer, which we have designated hMutLα. These observations indicate that interactions between members of the family of human MutL homologs may be restricted.

AB - Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the hMLHI gene. We have purified to near homogeneity an activity from HeLa cells that complements H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the eight base-base mismatches as well as a number of slipped- strand, insertion/deletion mispairs. This activity behaves as a single species during fractionation and copurifies with proteins of 85 and 110 kDa. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the hMLHI product and the latter to the product of hPMS2 or a closely related gene. The 1:1 molar stoichiometry of the two polypeptides and their hydrodynamic behavior indicate formation of a heterodimer, which we have designated hMutLα. These observations indicate that interactions between members of the family of human MutL homologs may be restricted.

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