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Different Mismatch Repair Deficiencies All Have the Same Effects on Somatic Hypermutation
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 1999
- Publisher :
- The Rockefeller University Press, 1999.
-
Abstract
- Somatic hypermutation of Ig genes is probably dependent on transcription of the target gene via a mutator factor associated with the RNA polymerase (Storb, U., E.L. Klotz, J. Hackett, Jr., K. Kage, G. Bozek, and T.E. Martin. 1998. J. Exp. Med. 188:689–698). It is also probable that some form of DNA repair is involved in the mutation process. It was shown that the nucleotide excision repair proteins were not required, nor were mismatch repair (MMR) proteins. However, certain changes in mutation patterns and frequency of point mutations were observed in Msh2 (MutS homologue) and Pms2 (MutL homologue) MMR-deficient mice (for review see Kim, N., and U. Storb. 1998. J. Exp. Med. 187:1729–1733). These data were obtained from endogenous immunoglobulin (Ig) genes and were presumably influenced by selection of B cells whose Ig genes had undergone certain mutations. In this study, we have analyzed somatic hypermutation in two MutL types of MMR deficiencies, Pms2 and Mlh1. The mutation target was a nonselectable Ig-κ gene with an artificial insert in the V region. We found that both Pms2- and Mlh1-deficient mice can somatically hypermutate the Ig test gene at approximately twofold reduced frequencies. Furthermore, highly mutated sequences are almost absent. Together with the finding of genome instability in the germinal center B cells, these observations support the conclusion, previously reached for Msh2 mice, that MMR-deficient B cells undergoing somatic hypermutation have a short life span. Pms2- and Mlh1-deficient mice also resemble Msh2-deficient mice with respect to preferential targeting of G and C nucleotides. Thus, it appears that the different MMR proteins do not have unique functions with respect to somatic hypermutation. Several intrinsic characteristics of somatic hypermutation remain unaltered in the MMR-deficient mice: a preference for targeting A over T, a strand bias, mutational hot spots, and hypermutability of the artificial insert are all seen in the unselectable Ig gene. This implies that the MMR proteins are not required for and most likely are not involved in the primary step of introducing the mutations. Instead, they are recruited to repair certain somatic point mutations, presumably soon after these are created.
- Subjects :
- Genome instability
Male
congenital, hereditary, and neonatal diseases and abnormalities
DNA Repair
Base Pair Mismatch
DNA mismatch repair
Immunology
Molecular Sequence Data
Restriction Mapping
Immunoglobulin Variable Region
Somatic hypermutation
Biology
transgenic mice
03 medical and health sciences
Mice
0302 clinical medicine
Immunology and Allergy
Animals
Transgenes
030304 developmental biology
Adaptor Proteins, Signal Transducing
Genetics
Mice, Knockout
0303 health sciences
B-Lymphocytes
Base Sequence
Point mutation
Nuclear Proteins
Molecular biology
digestive system diseases
somatic hypermutation
Neoplasm Proteins
MSH2
immunoglobulin genes
Codon, Terminator
Immunoglobulin heavy chain
Original Article
Female
Carrier Proteins
Immunoglobulin Heavy Chains
MutL Protein Homolog 1
030215 immunology
Nucleotide excision repair
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 190
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....5937c1436bdab555252608aa01b0d361