Thesis and Guide details:
Details of CSIR Fellowship/ Associateship held, if any or from other sources/ agencies.
Significant foreign assignments:
(a) Significant contributions to science and/ or technology development by the nominee
based on the work done in India during most part of last 5 years:
The major scientific contributions of Dr. Sanjeev Das are in the field of cancer biology. Dr. Das has
worked extensively on understanding the regulatory milieu of tumor suppressors, the proteins that
regulate diverse processes underlying tumorigenesis (Molecular Cell, 2011; Cell, 2007). The focus of Dr.
Das's work in the last five years has been on p53 family of tumor suppressors and sirtuins. Using mass
spectrometry based approaches, they identified various proteins with which p53 interacts to initiate the
stress response process, one of them being HDAC5 (Histone Deacetylase 5). Their studies demonstrated
that HDAC5 is a deacetylase that plays a key role in regulating p53 acetylation status, which has
immense influence on its target selection. Thus HDAC5 plays a key role in modulating p53-mediated
genotoxic stress response that augments prosurvival functions of p53 over apoptosis by promoting
preferential transactivation of p53 proarrest and antioxidant target genes (Molecular Cell, 2013). This
was the first study demonstrating the temporal regulation of a key p53 posttranslational modification that
determines p53-mediated transactivation and cell fate decisions. Using proteomics approach, they also
identified novel interacting proteins of the p53 family member p73 such as ubiquitin ligase TRIM28 and
transcriptional coactivator Med15. They reported that TRIM28 polyubiquitylates p73 specifically in
unstressed conditions, resulting in p73 degradation. Upon genotoxic stress p73 gets phosphorylated
leading to abrogation of its interaction with TRIM28 resulting in p73 stabilization. Furthermore, the
phosphorylated form of p73 specifically interacts with MED15 which serves as a transcriptional
coactivator and promotes anti-metastatic functions of p73 (Oncogene, 2016). These findings enhance
our understanding of the role of posttranslational modifications in p53 family-mediated response to
chemotherapy. Furthermore, their studies have also revealed the molecular mechanisms underlying the
tumor suppressor functions of sirtuin family member SIRT6. They mapped the SIRT6 interactome and characterized two key interacting proteins viz. PKM2 and UBE3A. They demonstrated that SIRT6 binds to
and deacetylates nuclear PKM2 (Pyruvate kinase M2), a glycolytic enzyme with non-metabolic nuclear
protein kinase and transcriptional coactivator functions. SIRT6-mediated deacetylation results in PKM2
nuclear export. They further identified exportin 4 as the specific transporter mediating PKM2 nuclear
export. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional
coactivator functions are abolished. Thus SIRT6 suppresses PKM2 oncogenic functions. Furthermore,
reduced SIRT6 levels correlate with elevated nuclear acetylated PKM2 levels in increasing grades of
hepatocellular carcinoma (PNAS, 2016). On the other hand, UBE3A ubiquitylates SIRT6 leading to its
proteasomal degradation thereby promoting aggressive tumor phenotype in hepatocellular carcinoma
(Oncogene, 2017). These findings provide key insights into SIRT6 tumor suppressor functions and
regulation.
In conclusion, the work from Dr. Das's laboratory has led to a keen understanding of tumor
suppressor proteins. His work provides mechanistic insights on regulatory and metabolic perturbations
intrinsic to tumorigenesis. It also highlights the vulnerabilities in tumor cell biology which could be
exploited for therapeutic interventions that bring about a positive clinical outcome.
(b) Impact of the contributions in the field concerned:
p53 is an attractive target in combating cancer due to the high potency of p53-mediated tumor
suppression, including growth arrest and induction of apoptosis, inhibition of angiogenesis, as well as
blocking invasion and metastasis. The work from Dr. Das's laboratory established that tight regulation of
p53 posttranslational modifications is a key determinant of p53-mediated cell fate decisions. Through
chemical genetics and high throughput screening based approaches small molecules can be developed
to regulate the p53 modifying enzymes such as that p53 proapoptotic functions are potentiated. These
can be combined with traditional chemo- and radiation therapy based regimens to increase their tumor
clearance efficacy.
New roles of p53 are immensely reshaping the multifarious facets of metabolism. Given the
current understanding of tumor metabolism, there is an opportunity to generate a new class of anti-tumor
drugs that target altered metabolism in cancer cells. There are differences between normal cell
metabolism and cancer cell metabolism that provide clinically relevant therapeutic windows. The findings
from Dr. Das's laboratory help in identifying the therapeutic windows for targeting cancer cell metabolism
due to the addiction of cancer cells to specific nutrients to support deregulated cell growth programs
enforced by cancer genes. Elucidating the pathways by which p53 coordinates metabolic adaptation
could establish new therapeutic targets in cancers that express wild-type p53. The relative contribution of
each of the many p53 metabolic target genes might differ according to cell type, stress signal and other
circumstances, and it is quite likely that not all p53 targets will be equally important to the final response.
Furthermore, whether a p53 target gene responds to high or low stress is also likely to depend very much
on the tissue in which the response is activated, and on the type of stress signal activating it. However,
increased understanding of the role of p53 in metabolism will provide a rich harvest of new therapeutic
targets.
The function of the guardian of the genome, p53, is often compromised in cancers. Due to the
high structural and functional homology to p53, regulation of p73 function represents a unique approach
for targeted cancer therapy. p73 can potentially be induced or activated to replace inactive p53 for
induction of cell cycle arrest/apoptosis. The work from Dr. Das's laboratory enhances the understanding
of p73 interactome. It delineates the mechanisms determining p73 protein stability and functions. This
enables the development of new cancer therapeutics for cases where p53 functions are compromised
and p73 can be activated to bring about tumor regression.
Previous studies have demonstrated that SIRT6 plays critical roles in maintaining genomic
stability and metabolic homeostasis, thereby impacting several pathways pertinent to cancer, metabolism
and aging. Dr. Das's work throws light on SIRT6 regulation and the crosstalk between SIRT6 and other
metabolic regulators. His findings present an in-depth analysis of transcriptional regulation of metabolic
processes and provide a robust platform for further studies to fully discover the activities of this important
chromatin protein in mammalian pathophysiology. Since metabolic reprogramming is intrinsic to
tumorigenesis, his work helps to understand how modulating SIRT6 activity could provide therapeutic
benefits under conditions of metabolic imbalance observed in tumors.
Places where work of last 5 years has been referred/ cited in Books, Reviews:
Names of the industries in which the technology (ies) has (have) been used :
The achievements already been recognised by Awards by any learned body:
The Awardee a fellow of the Indian National Science Academy/Indian Academy of Sciences/National
Academy of Sciences/Others:
The Awardee delivered invited lecture(s) in India/abroad and/or chaired any scientific
Internatiional Conference Symposium:
List of Awardee's 10 most significant publications.
List of Awardee's 5 most significant publications during the last 5 years
List of Awardee's 5 most significant publications from out of work done in India
during the last five years:
Complete list of publications in standard refereed journals:
Complete list of publications with foreign collaborators (indicating your status
as author):
List of papers published in Conferences /Symposia/ Seminars, etc:
List of the most outstanding Technical Reports/ Review Articles:
Statement regarding collaboration with scientists abroad:
Total number of patents granted in last five years.
Details of Books published: