Nucleotide excision repair (NER) and DNA mismatch repair are required for some common processes although the biochemical basis for this requirement is unknown. Saccharomyces cerevisiae RAD14 was identified in a two-hybrid screen using MSH2 as ''bait,'' and pairwise interactions between MSH2 and RAD1, RAD2, RAD3, RAD10, RAD14, and RAD25 subsequently were demonstrated by two-hybrid analysis. MSH2 coimmunoprecipitated specifically with epitope-tagged versions of RAD2, RAD10, RAD14, and RAD25. MSH2 and RAD10 were found to interact in msh3 msh6 and mlh1 pms1 double mutants, suggesting a direct interaction with MSH2. Mutations in MSH2 increased the UV sensitivity of NER-deficient yeast strains, and msh2 mutations were epistatic to the mutator phenotype observed in NER-deficient strains. These data suggest that MSH2 and possibly other components of DNA mismatch repair exist in a complex with NER proteins, providing a biochemical and genetical basis for these proteins to function in common processes.Eukaryotes contain a DNA mismatch repair (MMR) system involving proteins related to the bacterial MutS and MutL proteins (for a review see ref. 1). The eukaryotic MMR system is more complex than the bacterial system. Instead of involving a single MutS-related protein, eukaryotic MMR involves two different heterodimeric complexes of MutS-related proteins, MSH2-MSH3 and MSH2-MSH6, that each have different mispair recognition specificity (1-7). Similarly, instead of a single MutL-related protein, eukaryotic MMR also involves a heterodimeric complex of two MutL-related proteins, MLH1-PMS1 (PMS2 in humans) (8,9). Initial characterization of these pathways concentrated on their function in correcting mispaired bases resulting from DNA replication errors and the formation of heteroduplex recombination intermediates. Subsequent studies have suggested that MMR proteins may play more diverse roles in DNA metabolism.MMR plays roles in genetic recombination beyond the repair of mispaired bases in recombination intermediates. MMR appears to regulate the extent of formation of heteroduplex tracts during recombination (10-12), possibly by regulating the resolution of Holliday junctions (11). MMR also suppresses recombination between divergent sequences (13-16), a process that may be similar to the proposed regulation of heteroduplex tract formation. The MSH2 and MSH3 proteins also act in recombination between duplicated DNA sequences (17, 18) and have been implicated in the removal of nonhomologous DNA strands greater than 30 bases long at the ends of recombining segments (19). This reaction involves the nucleotide excision repair (NER) complex 21). It is unclear how MMR proteins function in these reactions; however, the ability of MSH2 and the MSH2-MSH6 complex to bind to Holliday junctions and branched DNA structures (ref. 22 and G. T. Marsischky, S. Lee, J. Griffith, and R.D.K., unpublished results) suggest they could bind to branched DNA structures and either target resolution enzymes and endonucleases to these structures or al...
After segmentation of the vertebrate hindbrain, expression of the zinc-finger gene Krox-20 and the receptor tyrosine kinase gene Sek-1 is precisely restricted to rhombomeres (r) 3 and 5. This precise segmental expression is likely to reflect a critical requirement for these rhombomeres to acquire a distinct and homogeneous identity and raises the question as to how this relates to the intermingling and restriction of cell movement during segmentation. We have analysed Krox-20 and Sek-1 expression in the mouse and chick hindbrain at single-cell resolution using whole-mount in situ hybridisation and immunocytochemistry. We find that, in the mouse, the presumptive r3 and r5 expression domains each arise as narrow stripes that then broaden, suggestive of a recruitment of cells to an r3/r5 identity and/or a segmental regulation of cell proliferation. In addition, we find that expression of these genes initially occurs in fuzzy domains, and that these are progressively restricted to segmental domains, although occasional "violating" cells are observed even after segmentation. We propose that the establishment and maintenance of these segmental domains may involve both a dynamic regulation of r3/r5 identity and the restriction of cell movement across rhombomere boundaries.
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