Hypermutability and mismatch repair deficiency in RER+ tumor cells

Ramon Parsons, Guo Min Li, Matthew J. Longley, Woei horng Fang, Nickolas Papadopoulos, Jin Jen, Albert de la Chapelle, Kenneth W. Kinzler, Bert Vogelstein, Paul Modrich

Research output: Contribution to journalArticle

909 Citations (Scopus)

Abstract

A subset of sporadic colorectal tumors and most tumors developing in hereditary nonpolyposis colorectal cancer patients display frequent alterations in microsatellite sequences. Such tumors have been thought to manifest replication errors (RER+), but the basis for the alterations has remained conjectural. We demonstrate that the mutation rate of (CA)n repeats in RER+ tumor cells is at least 100-fold that in RER- tumor cells and show by in vitro assay that increased mutability of RER+ cells is associated with a profound defect in strand-specific mismatch repair. This deficiency was observed with microsatellite heteroduplexes as well as with heteroduplexes containing single base-base mismatches and affected an early step in the repair pathway. Thus, a true mutator phenotype exists in a subset of tumor cells, the responsible defect is likely to cause transitions and transversions in addition to microsatellite alterations, and a biochemical basis for this phenotype has been identified.

Original languageEnglish (US)
Pages (from-to)1227-1236
Number of pages10
JournalCell
Volume75
Issue number6
DOIs
StatePublished - Dec 17 1993
Externally publishedYes

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Tumors
Repair
Cells
Microsatellite Repeats
Neoplasms
Phenotype
Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Mutation Rate
Defects
Colorectal Neoplasms
Turcot syndrome
Assays

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Parsons, R., Li, G. M., Longley, M. J., Fang, W. H., Papadopoulos, N., Jen, J., ... Modrich, P. (1993). Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell, 75(6), 1227-1236. https://doi.org/10.1016/0092-8674(93)90331-J

Hypermutability and mismatch repair deficiency in RER+ tumor cells. / Parsons, Ramon; Li, Guo Min; Longley, Matthew J.; Fang, Woei horng; Papadopoulos, Nickolas; Jen, Jin; de la Chapelle, Albert; Kinzler, Kenneth W.; Vogelstein, Bert; Modrich, Paul.

In: Cell, Vol. 75, No. 6, 17.12.1993, p. 1227-1236.

Research output: Contribution to journalArticle

Parsons, R, Li, GM, Longley, MJ, Fang, WH, Papadopoulos, N, Jen, J, de la Chapelle, A, Kinzler, KW, Vogelstein, B & Modrich, P 1993, 'Hypermutability and mismatch repair deficiency in RER+ tumor cells', Cell, vol. 75, no. 6, pp. 1227-1236. https://doi.org/10.1016/0092-8674(93)90331-J
Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 1993 Dec 17;75(6):1227-1236. https://doi.org/10.1016/0092-8674(93)90331-J
Parsons, Ramon ; Li, Guo Min ; Longley, Matthew J. ; Fang, Woei horng ; Papadopoulos, Nickolas ; Jen, Jin ; de la Chapelle, Albert ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Modrich, Paul. / Hypermutability and mismatch repair deficiency in RER+ tumor cells. In: Cell. 1993 ; Vol. 75, No. 6. pp. 1227-1236.
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