Dr. Rajesh Kumar Yadav
Epigenetics, Cancer biology, Onco-histone mutation, DNA Damage Response, Immunotherapy, Host-parasite interaction, Leishmaniasis
According to global cancer statistics 2020, the global cancer burden is expected to rise 47% from 2020 to 2040. Due to changing socio-economic scenario and sedentary lifestyle, the Indian cancer burden is also on the rise, therefore an urgent research investment in the cancer field is the need for better-personalized drug development. Tumorigenesis is an evolving multistep process involving genetic and epigenetic changes that provide a growth advantage to cancer cells over normal cells. The next-generation genome sequencing of cancer cells has identified new recurrent mutations, but the exact biological effects of those mutations are unknown. Our laboratory primarily applies biochemistry, molecular cell biology, genetic and epigenetic approaches to study such mutations in proteins and DNA-protein complexes. Nucleosome remodelers, chromatin modifiers(writers, erasers), and readers of histone and DNA modifications are frequently altered in cancer. However, the oncogenic nature and mechanisms of histone mutations itself in cancer are not clear. Histones are not only the packaging material of eukaryotic DNA but also control the dynamic nature of chromatin, essential for replication, transcription, and DNA repair. We are applying the diverse techniques to study the following topics:
1. The role of “Readers” and “Erasers” proteins in the DNA Damage Response (DDR) pathway
We are focusing on demethylases and bromodomain proteins, to identify novel synthetic lethal genetic interactions of “readers/writers “protein with DDR pathway genes.
2. Understanding the oncogenic and biological effect of cancer-associated histone H3 and H4 mutations
Very high-frequency somatic heterozygous missense mutations in histone H3 genes at highly conserved amino terminus residues (K27, K36 and G34) were reported in pediatric high-grade gliomas, sarcomas, head-neck cancers, and carcinosarcomas as well as many adult cancers. H3.3K27M oncohistone reduces repressive histone modification marks, H3K27 trimethylation in trans by altering activities of polycomb repressive complex 2, thus interfering with the developmentally regulated genes whereas H3.3G34R mutation reduces activating mark, H3K36me3 in cis. These mechanisms suggest alteration in gene expression pattern and may contribute toward tumorigenesis. On the other hand, few studies argue that tumorigenesis may likely occur due to genomic instability caused by H3.3K27M and H3.3G34R oncohistones. How differential PTMs of H3K36 and H3K27 may impact genome stability is not clear. Also, the common mechanism of oncohistone mutants (H3.3K27M and H3.3G34R) toward genome instability is elusive.
3. Identifying functions of histone demethylases to enhance the antitumor potential of chimeric antigen receptor (CAR) T cell
CAR T cell therapy is successful in hematological cancers but its potential for solid tumors needs further extensive research. Therefore, our lab has a growing interest in combination therapy to improve tumor resistance against CAR T cells.
Ramalingaswami Re-entry Fellowship, Department of Biotechnology, Government of India (2017-2018)
- Yadav RK*, Matsuda A*, Lowe BR, Hiraoka Y, Partridge JF. Subtelomeric Chromatin in the Fission Yeast S. pombe. Microorganisms.2021; 9(9):1977. *Authors contributed equally to this work
- Lowe BR, Yadav RK, Henry RA, Schreiner P, Matsuda A, Fernandez AG, Finkelstein D, Campbell M, Kallappagoudar S, Jablonowski CM, Andrews AJ, Hiraoka Y, Partridge JF. Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail. eLife. 2021 Feb 1; 10: e65369, PMID: 33522486
- Yadav RK, Ali A, Kumar S, Sharma A, Baghchi B, Singh P, Das S, Singh C, Sharma S. CAR T cell therapy: newer approaches to counter resistance and cost. Heliyon. 2020 Apr 16; 6(4):e03779. PMID: 32322738
- Yadav RK, Jablonowski CM, Fernandez AG, Lowe BR, Henry RA, Finkelstein D, Barnum KJ, Pidoux AL, Kuo YM, Huang J, O'Connell MJ, Andrews AJ, Onar-Thomas A, Allshire RC, Partridge JF. Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe. eLife. 2017 Jul 18; 6: e27406. PMID: 28718400
- Kallappagoudar S*, Yadav RK*, Lowe BR*, Partridge JF Histone H3 mutations-a special role for H3.3 in tumorigenesis? Chromosoma. 2015 Jun;124(2):177-89 PMID:25773741*Authors contributed equally to this work
- Alper BJ, Job G, Yadav RK, Shanker S, Lowe BR, Partridge JF. Sir2 is required for Clr4 to initiate centromeric heterochromatin assembly in fission yeast. EMBO J. 2013 Aug 28;32(17):2321-35 PMID:23771057
- Yadav RK, Pal S, Dolai S, Adak S. Role of proximal methionine residues in Leishmania major peroxidase. Arch Biochem Biophys. 2011 Nov;515 (1-2) (Cover article) PMID:21893024
- Dolai S, Pal S, Yadav RK, Adak S. Endoplasmic reticulum stress-induced apoptosis in Leishmania through Ca2+-dependent and caspase-independent mechanism. J Biol Chem. 2011 Apr 15; 286 (15):13638-46. PMID:21330370
- Pal S, Dolai S, Yadav RK, Adak S Ascorbate peroxidase from Leishmania major controls the virulence of infective stage of promastigotes by regulating oxidative stress. PLoS One. 2010 Jun 23; 5(6): e11271. PMID:20585663
- Yadav RK, Dolai S, Pal S, Adak S Role of tryptophan-208 residue in cytochrome c oxidation by ascorbate peroxidase from Leishmania major-kinetic studies on Trp208Phe mutant and wild type enzyme. Biochimica et Biophysica Acta - Proteins and Proteomics 2008 May; 1784(5): 863-71. PMID:18342641