hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6.
The genetic and biochemical properties of three human MutS homologues, hMSH2, hMSH3, and hMSH6, have been examined. The full-length hMSH6 cDNA and genomic locus were isolated and characterized, and it was demonstrated that the hMSH6 gene consisted of 10 exons and mapped to chromosome 2p15-16. The hMSH3 cDNA was in some cases found to contain a 27-bp deletion resulting in a loss of nine amino acids, depending on the individual from which the cDNA was isolated. hMSH2, hMSH3, and hMSH6 all showed similar tissue-specific expression patterns. hMSH2 protein formed a complex with both hMSH3 and hMSH6 proteins, similar to protein complexes demonstrated by studies of the Saccharomyces cerevisiae MSH2, MSH3, and MSH6. hMSH2 was also found to form a homomultimer complex, but neither hMSH3 nor hMSH6 appear to interact with themselves or each other. Analysis of the mismatched nucleotide-binding specificity of the hMSH2-hMSH3 and hMSH2-hMSH6 protein complexes showed that they have overlapping but not identical binding specificity. These results help to explain the distribution of mutations in different mismatch-repair genes seen in hereditary nonpolyposis colon cancer.
Acharya
S
S
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Wilson
T
T
Gradia
S
S
Kane
M F
MF
Guerrette
S
S
Marsischky
G T
GT
Kolodner
R
R
Fishel
R
R
D001483:Base Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D003001:Cloning, Molecular; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D017931:DNA Primers; D004260:DNA Repair; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005656:Fungal Proteins / Q000378:metabolism*; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009838:Oligodeoxyribonucleotides; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D017384:Sequence Deletion; D013379:Substrate Specificity; D014158:Transcription, Genetic
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C081696:MSH3 protein, S cerevisiae; C098790:MSH6 protein, S cerevisiae; D000074081:MutS Homolog 3 Protein; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein