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Meiosis is a key process for sexually reproducing eukaryotes and generates haploid gametes from a diploid cell. Here, a single round of DNA replication is followed by two rounds of chromosome segregation. A unique aspect of chromosome behavior in meiosis is the pairing and segregation of homologous chromosomes that requires physical connections between them that is mediated via genetic recombination during meiotic prophase. The homologous chromosomes segregate to the opposite poles during the first meiotic division (meiosis I), while the sister chromatids segregate at the second meiotic division (meiosis II). Understanding the mechanisms for proper segregation of chromosomes is clinically important because chromosome missegregation during meiosis is a major cause of human miscarriage and trisomies such as Down syndrome.
Research Interests
Meiotic recombination and centromeres
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The centromere is a principal player involved in chromosomal segregation during cell division. A complex network of centromeric proteins allow error-free segregation during meiosis, while specifically preventing meiotic recombination. Inappropriate double-strand breaks (DSBs) and subsequent recombination at the centromeres increase chromosomal missegregation and generation of aneuploid spores upon meiosis. The molecular mechanism of how breaks and recombination are repressed at centromeres is only recently being worked out in different experimental systems especially in yeasts. Recent work in fission yeast S. pombe has demonstrated the important roles of cohesins and heterochromatin in this repression, and this mechanism may also be conserved in humans owing to conservation of centromere structure, heterochromatin and cohesins. However, how centromeric recombination generates aneuploid gametes upon completion of meiosis, as has been implicated in humans, is unclear.
Cohesin complexes and heterochromatin
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Sister chromatid cohesion is important for accurate chromosome segregation during both mitosis and meiosis and is achieved by cohesin, a ring-shaped protein complex that topologically entraps both sister chromatids. We are interested in exploring the mechanisms that generate errors in chromsomal segregation during cell division particularly focusing on the roles of the centromeric cohesins and heterochromatin. This study will have implications not only in human infertility as well as developmental disorders such as Down and Edward syndrome and other trisomies but also in other congenital genetic diseases such as Cornelia de Lange syndrome where cohesin loading is defective.
Cohesins and cancer
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Cohesins are commonly mutated in different cancers and have been implicated in the generation of aneuploidy and genomic instability, which can eventually result in tumorigenesis. However, the complete spectrum of tumors harboring cohesin mutations and the precise functional significance of cohesin mutations in the pathogenesis of specific tumor types remain undefined. Apart from mutations in the cohesin subunits and their regulators, the aberrant expression of meiosis-specific cohesins are also observed in a variety of cancers. Understanding their molecular interactions in mitotic cells is pertinent to get a clear picture of how they affect cellular activities.