WELCOME TO THE
CHROMATIN REMODELING LABORATORY (CRL)

JNU SLS CRL RESEARCH PEOPLE COURSES CONTACT

The DNA in eukaryotic cells is tightly packaged so that it can be accommodated within the tiny nucleus. This packaging acts as roadblock for DNA repair, replication and transcription. The DNA, is therefore, made accessible as and when required by a process known as chromatin remodeling.

In my laboratory, we study ATP-dependent chromatin remodeling mediated by the SWI2/SNF2 proteins. These proteins belong to the SF2 class of helicases and use the energy released by ATP hydrolysis to reposition nucleosomes.

There are three major focus areas:

  1. Mechanism of ATP hydrolysis by ATP-dependent chromatin remodeling proteins. The ATP-dependent chromatin remodeling proteins possess the seven helicase motifs characteristic of helicases even though they do not show any helicase activities. We have been engaged in understanding the role of these motifs vis-à-vis ATP and DNA binding using biophysical and biochemical tools.

  2. Functional characterization of SMARCAL1 and FUN30: SMARCAL1 is a distant member of the ATP-dependent chromatin remodeling protein family. Studies have shown that it is required for DNA repair in mammalian cells. We are exploring the role of this protein in mammalian cells beyond DNA repair using cell biology tools.

    Recently, we have cloned FUN30 protein from C. albicans, which is homologous to the FUN30 protein present in S. cerevisiae. We are now delineating the function of this protein in the pathogenic organism C. albicans.

  3. Understanding the how the regulators are regulated: The ATP-dependent chromatin remodeling proteins regulate gene expression by repositioning nucleosomes. But how are these proteins themselves regulated? We have shown that SMARCAL1 and BRG1 transcriptionally regulate each other when HeLa cells are treated with doxorubicin. This is the smallest co-regulatory loop involving two ATP-dependent chromatin remodeling proteins. We are now trying to understand why these two proteins regulate each other. We are also attempting to delineate other such loops involving ATP-dependent chromatin remodeling proteins.

PUBLICATIONS:

  • Haokip, D.T., Goel, I., Arya, V., Sharma, T., Kumari, R., Priya, R., Singh, M., and Muthuswami, R., Transcriptional regulation of ATP-dependent chromatin remodeling factors: SMARCAL1 and BRG1 mutually co-regulate each other (2016) Scientific Reports (Manuscript accepted for publication).
  • Sharma, T., Bansal, R., Haokip, D.T., and Muthuswami, R., SMARCAL1 negatively regulates c-myc transcription by altering the conformation of the promoter region (2015). Scientific Reports 5:17910.
  • Gupta, M., Mazumdar, M., Datchinamoorthy, K., Gourinath, S., Nongkhlaw, M., Komath, S.S., and Muthuswami, R., Ligand induced conformational changes drive ATP hydrolysis in SMARCAL1 (2015). FEBS J. 282: 3841-3859.
  • Tanti,G.K., Singarapu, N., Muthuswami, R., and Goswami, S.K., Among the three striatin family members, SG2NA was first to arise during evolution (2014). Front. Biosci. (Schol. Ed.) 6: 1-15
  • Dutta, P., Tanti, G.K, Sharma, S., Goswami, S.K., Komath, S.S., Mayo, M.W., Hockensmith, J.W., and Muthuswami, R., Global epigenetic changes induced by SWI2/SNF2 inhibitors characterize neomycin resistant mammalian cells. (2012), PLoS One. 7(11): e49822.
  • Nongkhlaw, M., Gupta, M., Komath, S.S., and Muthuswami, R. Motifs Q and I are required for ATP hydrolysis but not for ATP binding in SWI2/SNF2 proteins. (2012) Biochemistry, 51: 3711-22.
  • Ahmad M.F., Yadav B., Kumar P., Puri A., Mazumder M., Ali A., Gourinath S., Muthuswami R., Komath SS. The GPI anchor signal sequence dictates the folding and functionality of the Als5 adhesin from Candida albicans. (2012) PLoS One 7 (4): e35305
  • Ashraf, M., Yadav, B., Sreejith, P., Kumar, S. K., Vats, D., Muthuswami, R. and Komath, S.S. (2011), The N-acetyl-D-glucosaminylphosphotidylinositol de-N-acetylase from Entamoeba histolytica: Metal alters catalytic rates but not substrate affinity. J. Biol. Chem., 286: 2543-2549.
  • Nongkhlaw, M., Dutta, P., Hockensmith, J.W., Komath, S.S., and Muthuswami, R., Elucidating the mechanism of DNA-dependent ATP hydrolysis by DNA-dependent ATPase A, a member of the SWI2/SNF2 protein family (2009). Nucleic Acids Res. 37, 3332-41.
  • Oswal, N., Sahni, N.S., Bhattacharya, A., Komath, S.S., Muthuswami, R., (2008), Unique motifs identify PIG-A proteins from glycosyltransferases of the GT4 family. BMC Evol Biol. 8, 168
  • Muthuswami, R., Burnett, B.B., Thimmig, R.L., and McHenry, C.S., (2002) The HIV Plus-Strand Transfer Reaction: Stimulation by Nucleocapsid Protein and Identification of a Novel Lentiviral Element, the Primer Overextension Sequence, J. Mol. Biol., 315, 311-23#
  • Muthuswami, R.., Truman, P.A., Mesner, L.D., and Hockensmith, J.W., (2000), A Eukaryotic SWI2/SNF2 Domain, an Exquisite Detector of Double-stranded to Single-stranded DNA Transition Elements, J.Biol.Chem., 275, 7648-7655.
  • Muthuswami, R.., Mesner, L.D., Wang, D., Hill, D.A., Imbalzano, A.N., and Hockensmith, J.W., (2000), Phosphoaminoglycosides Inhibit SWI2/SNF2 Family of DNA-dependent Molecular Motor Domains, Biochemistry, 39, 4358-4365.