Goa University, Goa, India
University of Delhi, Delhi, India
Harvard Medical School & UVA
DNA replication is a vital process of life and must be completed precisely during each cell cycle. When mammalian cell experiences DNA damage, it activates checkpoint mechanisms to stall the progression of cell cycle and DNA replication. Our laboratory is interested in understanding the mechanisms by which microRNA and checkpoint proteins stall the cell cycle preventing genomic instability and cancer.
Akhil Varshey, Sunder Bisht, Md. Muntaz Khan, Ananya Kar, Manpreet Kaur, Tanushree Ghosh, Aishana Singh, Shalini Dimri, Rashmi Bhakuni
Summary of Research
The research interest of the laboratory is in the following areas:
Role of non-coding RNAs in regulation of cell-cycle and DNA replication:Emerging evidences suggest that microRNA target genes that regulate DNA replication and cell cycle progression and we aim to determine how microRNA regulate the DNA replication machinery as cell progresses from one phase to the next. Aberrations in microRNA activity has been linked to loss of cell cycle and replication control and this has led to oncogenic functions (thereby called oncomirs) being ascribed to them. Summing up, we are trying to understand the mechanisms by which microRNAs regulate mammalian cell cycle and DNA replication in normal and pathological conditions.
Understanding the checkpoint response to aberrations in replication complexes: Whenever genomic lesions are detected during DNA synthesis, they are coated by the single strand DNA binding protein complex, called Replication Protein A, leading to the activation of canonical checkpoint proteins like ATR, Chk1 and p53. Human genome codes for many other single strand DNA binding proteins and we are testing if novel mechanisms of checkpoint activation exist that do not require Replication Protein A. If such mechanisms exist we would like to understand which factors provide the role of DNA binding, how checkpoint proteins like Chk1 and p53 are activated and how signal transduction pathway stalls the cell cycle and DNA replication.
Regulation of replication machinery during stress: It is known that replication factors are downregulated during stress and we have observed that cullin 4-based ubiquitin ligase mediate the proteolysis of Mcm10, a protein essential for the initiation and elongation phases of DNA replication. Therefore, we are trying to understand the independent mechanism by which mammalian cells effectively inhibit the replication machinery during stress preventing it from drifting towards a catastrophic path of genomic instability. It has been observed that some replication proteins localize to the centrosome suggesting their role in regulation of centrosome biogenesis. Since it is well recognized that errors in the centrosome duplication contribute to tumorigenesis we are interested in determining the role of replication factors in preventing aneuploidy.
- Kaur, M., Khan, M. M., Kar, A., Sharma, A., and Saxena, S. (2012). CRL4-DDB1-VPRBP ubiquitin ligase mediates the stress triggered proteolysis of Mcm10. Nucleic Acids Research 40, 7332-7346.
- Sharma, A., Kaur, M., Kar, A., Ranade, S. M., and Saxena, S. (2010). Ultraviolet Radiation Stress Triggers the Down-regulation of Essential Replication Factor Mcm10. Journal of Biological Chemistry 285, 8352-8362.
- Saxena, S.*, Yuan, P.*, Dhar, S.K.*, Senga, T., Takeda, D., Robinson, H., Kornbluth, S.A., Swaminathan, K., & Dutta, A. (2004). A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition. Molecular Cell 15: 245-258. *Co-first-authors
- Vaziri, C.*, Saxena, S.*, Jeon, Y., Lee, C., Murata K.M., Machida, Y., Wagle, N., Hwang, D.S., Dutta, A. (2003). A p53 dependent checkpoint pathway prevents re-replication. Molecular Cell 11: 997-1008. *Co-first-authors