Sudhakar JHA

sudhakar_jha_on

Down-regulation of tumor suppressors or expression of oncogenes is a hallmark feature of cancers. These alterations in the transcriptome arise as a consequence of a malfunction in the chromatin organization. Chromatin remodeling complexes play an important role in maintaining this organization as they create a histone code that is read by specific readers resulting in an active or repressed chromatin. Dr Jha is interested in studying the regulation of chromatin remodeling complexes and their role in cancer prevention. His research focuses on understanding the function of TIP60 (a histone acetyltransferase) as a tumor suppressor. Dr Jha has discovered TIP60 to be down-regulated by E6, a viral oncogene expressed by human papillomavirus (HPV). Interestingly, TIP60 is down-regulated in multiple cancers. Using TIP60 as a candidate molecule, he plans to investigate how deregulation of this chromatin remodeling complex can lead to cancer.

Chromatin remodeling complexes play an important role in maintaining chromatin organization as they create a histone code that is read by specific readers resulting in an active or repressed chromatin. We are interested in understanding the regulation of chromatin remodeling complexes and their role in cancer prevention and intervention. We have purified and characterized chromatin remodeling complexes implicated in transcription and DNA damage response(Mol Cell 2009, 34: 521-533). We have identified the role of TIP60, a histone acetyltransferase in DNA damage response pathway (Mol Cell Biol 2008, 28: 2690-2700) and RVB1, a component of TIP60 complexes to be required for activity of this complex (Mol Cell Biol 2013, 33: 1164-74). In addition to purifying and characterizing these chromatin-remodeling complexes, we have also identified viral and cellular regulators of TIP60, a tumor suppressor. We have discovered viral oncogenes such as, Human Papillomavirus (HPV) E6 and Adenovirus (AdV) to destabilize TIP60 (Mol Cell 2010, 38: 700-711 and Oncogene 2013, 32: 5017-25) and also discovered an oncogenic mircoRNA (miR-22) to target mRNA of TIP60 (Oncotarget 2015, in press). Furthermore, we have identified the mechanism of TIP60 destabilization by E6, and its implications in cervical cancer progression (Oncogene 2015, in press). Currently, in the absence of an effective therapeutic vaccine, cervical cancer still remains to be a major disease burden. Hence, our group is focusing on investigating the role of TIP60 in cervical cancer progression as we have shown that reactivation of TIP60 could be of therapeutic value.

Selected Publications:

  1. E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60. Subbaiah VK, Zhang Y, Rajagopalan D, Abdullah LN, Yeo-Teh NS, Tomaić V, Banks L, Myers MP, Chow EK, Jha S. Oncogene. 2015 Aug 3. doi: 10.1038/onc.2015.268. [Epub ahead of print]
  2. TIP60-miR-22 axis as a prognostic marker of breast cancer progression. Pandey AK, Zhang Y, Zhang S, Li Y, Tucker-Kellogg G, Yang H, Jha S. Oncotarget. 2015 Oct 19. doi: 10.18632/oncotarget.5636. [Epub ahead of print]
  3. Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Gupta A, Jha S, Engel DA, Ornelles DA, Dutta A. Oncogene. 2013 Oct 17;32(42):5017-25
  4. RVBs are required for assembling a functional TIP60 complex. Jha S*, Gupta A*, Dar A, Dutta A. Mol Cell Biol. 2013 Mar;33(6):1164-74.*Co-first authors
  5. CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Abbas T, Shibata E, Park J, Jha S, Karnani N, Dutta A. Mol Cell. 2010 Oct 8; 40(1):9-21
  6. Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway. Jha S, Vande Pol S, Banerjee NS, Dutta AB, Chow LT, Dutta A. Mol Cell. 2010 Jun 11;38(5):700-11. (Highlight: “Faculty of 1000 Biology”, 17th June 2010)
  7. RVB1/RVB2: running rings around molecular biology. Jha S, Dutta A. Mol Cell. 2009 Jun 12;34(5):521-33.
  8. Architecture of the pontin/reptin complex, essential in the assembly of several macromolecular complexes. Torreira E, Jha S, López-Blanco JR, Arias-Palomo E, Chacón P, Cañas C, Ayora S, Dutta A, Llorca O. Structure. 2008 Oct 8;16(10):1511-20.
  9. Human Rvb1/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage. Jha S, Shibata E, Dutta A. Mol Cell Biol. 2008 Apr;28(8):2690-700.
  10. Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication. Zhu W*, Ukomadu C*, Jha S*, Senga T, Dhar SK, Wohlschlegel JA, Nutt LK, Kornbluth S, Dutta A. Genes Dev. 2007 Sep 15;21(18):2288-99.*Co-first authors
Name Sudhakar JHA
Affiliations Principal Investigator, Cancer Science Institute of Singapore, NUS
Assistant Professor, Department of Biochemistry, Yong Loo Lin School of Medicine, NUS
Email csisjha[at]nus.edu.sg  / bchsjha[at]nus.edu.sg

Education

Institute Degree (if applicable) Year(s)
Ewing Christian College, Allahabad University, Allahabad, India BSc 1998
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India Master of Science 2000
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India PhD 2003

Professional Experience

Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore 2011 – Present
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, USA 2003 – 2011

Shweta Pradip JADHAV

PhD
Research Fellow

Regulators of non-coding RNAs in cancer.

Amit Kumar PANDEY

PhD
Research Fellow

Investigating role of non-coding RNA in cancer.

Shainan HORA

PhD student

Developing models to study cell migration and metastasis.

Jha - James Kwok Kin Lee

LEE Kwok Kin James

PhD student

Identifying regulators of tumor suppressors.

LEONG Kim Bee Jean

PhD student

Chromatin organization and DNA damage response.

Deepa RAJAGOPALAN

PhD student

Identifying tumor suppressive pathways in virus-induced cancers.

YEO-TEH Shu Ling Nicole

PhD student

Identifying the transcriptional targets of TIP60.

ZHANG Siting

PhD student

Investigate breast cancer cell-type-specific TGF-β responsive synexpression and associated master-like transcription factors.

ZHANG Yan Zhou

PhD student

Identifying role of TIP60 in epithelial-mesenchymal transition (EMT).

THAM Cheng Yong

FYP student

Investigating the clinical significance of TIP60 mutations.