K. Muniyappa

Professor

Ph.D.

Indian Institute of Science, Bangalore, India. 1980

Postdoctoral Research

University of Georgia-Athens, U.S.A. 1981-1982
Yale University, U.S.A. 1982-1987
Tel: +91-80-22932235
Email: kmbc@biochem.iisc.ernet.in
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 Research

Our research focuses on understanding the molecular mechanisms underlying chromosome synapsis, homologous recombination, double stranded break repair and Fanconi anemia – the hereditary chromosomal instability disorder. Different experimental approaches currently are being used in the laboratory, which include genetics, functional and structural genomics, and model systems that range from bacteria to yeast to human cells.

  • Fanconi anemia and Homologous Recombination (HR)
  • Fanconi anemia (FA) is an autosomal recessive and X-linked genetic disorder characterized by congenital abnormalities, progressive bone marrow failure and pronounced cancer susceptibility. The FA-BRCA DNA damage response network is comprised of fifteen bonafide disease linked proteins, as well as numerous non FA proteins, that function cooperatively in DNA (ICL) repair.
    The hallmark of FA patient cells, as well as BRCA1/2- deficient cells, is hypersensitivity to the clastogenic effects of DNA cross- linking agents such as mitomycin C and cisplatin. Our research is aimed at elucidating the role of HR pathway components in FA cells.

  • Synaptonemal complex proteins of Saccharomyces cerevisiae
  • Synapsis of homologous chromosomes and normal levels of recombination during meiosis require the participation of synaptonemal complex (SC). However, whether SC plays an active or a scaffolding role has been the subject of ongoing debate. We are studying yeast HOP1 (for HOmolog Pairing), which encodes a component of SC, to understand the mechanisms of interstitial synapsis of homologous chromosomes and recombination. Previously, we showed that an oligomeric form of Hop1 binds cooperatively and preferentially to duplex DNA and modulates the processing of double-strand breaks. Recently, we found that Hop1 or its zinc-finger containing motif display higher affinity for the Holliday junction, consistent with its role in checkpoint control over the progression of meiotic recombination intermediates.

  • DNA Double Strand Break Repair (DSBR) of Saccharomyces cerevisiae
  • DNA Double Strand Breaks (DSBs) are the most deleterious forms of DNA lesions. If left unrepaired, they lead to cell death. If repaired improperly, they can lead to chromosome translocations and cancer. Homologous recombination and nonhomologous end joining are two predominant mechanisms of double strand break repair. The central step of homologous recombination is pairing and exchange of strand between two homologous DNA molecules which is catalyzed by conserved Rad51/RecA family of proteins. These enzymes require DNA substrates that are generated by a consortium of end resecting nucleases. Our research focuses on reconstituting the double-stranded end resection pathway of Saccharomyces cerevisiae. Additionally, we are trying to explore the role of homologous recombination proteins in the maintenance of genome integrity in Saccharomyces cerevisiae.

  • Mechanistic aspects of homologous pairing and stand exchange.
  • Using Escherichia coli RecA paradigm, we have contributed to understanding of the path of binding of RecA on DNA, "genome wide search" for homologous sequences, structural features of nucleoprotein filaments, and have introduced higher complexity to the biochemical issues of homologous recombination. Although much research has focused on immunology, biochemistry and microbiology of the tubercle bacillus, investigations into molecular interactions between specific gene products has not been possible because of lack of defined mutants with specific phenotypes. Therefore, understanding of the mechanistic aspects of homologous recombination may help molecular genetic manipulation of mycobacteria. To gain insights into mechanistic aspects of recombination and to elucidate the basis for inefficient allele exchange in the TB bacillus, molecular and structural approaches are being used to isolate the genes, overexpress proteins and study their biochemical functions. The interest in this area will expand to include comparative genomics to understand the phylogenetic relationship between pathogenic and non-pathogenic species of mycobacteria. It is hoped that the knowledge gained from these studies will enable us to reconstitute the pathway of homologous recombination in mycobacteria.

 Lab Members


 Publications