Mlh1 mediates tissue-specific regulation of mitotic recombination.
Mitotic recombination (MR) between chromosome homologs in somatic cells is a major pathway to the loss of heterozygosity (LOH), which may cause cancer if tumor suppressor genes are involved. MR can be suppressed by DNA sequence heterology (homeology) in hybrid mice from matings between species or between subspecies. We now report that MR is relatively suppressed in F1 hybrids between inbred strains C57BL/6 and 129S2. The frequency of MR in fibroblasts is lower in F1 hybrid mice than in either of the two parental strains. However, MR in T cells is not affected by strain background. Thus, relatively small genetic differences are capable of restricting MR in a tissue-specific manner. Using Mlh1-deficient mice, we tested the role of mismatch repair in MR in two isogenic cell types. In fibroblasts of C57BL/6 x 129S2 F1 mice, the suppression of MR is alleviated in the absence of MLH1. In contrast, MR is not affected by Mlh1 status in T cells. The frequency of point mutations at the reporter gene loci Aprt and Hprt, on the other hand, is significantly increased in both T cells and fibroblasts of Mlh1(-/-) mice. Thus, different cell types respond differently to MLH1 deficiency, and the contribution of MR to tumorigenesis may be tissue-dependent in the absence of mismatch repair.
Department of Genetics, Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082, USA. shao@biology.rutgers.edu
Changshun
C
Shao
Li
L
Deng
Yanping
Y
Chen
Raju
R
Kucherlapati
Peter J
PJ
Stambrook
Jay A
JA
Tischfield
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis / Q000502:physiology*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D017354:Point Mutation; D011995:Recombination, Genetic / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1