I. Discovery of a new Nonhistone Chromatin Organizer
Sikder S., Agrawal A., Singh S., Peraman R., Ravichandran V., Kundu T. Ko., KAT5 Acetylates Human Chromatin Protein PC4 to promote DNA Repair, (https://doi.org/10.1101/2024.01.12.575390).
Das C, Hizume K, Batta K, et al. Transcriptional Coactivator PC4, a Chromatin-Associated Protein, Induces Chromatin Condensation. Mol Cell Biol. 2006;26(22):8303-8315. doi:10.1128/mcb.00887-06
Mustafi P, Hu M, Kumari S, et al. Phosphorylation-dependent association of human chromatin protein PC4 to linker histone H1 regulates genome organization and transcription. Nucleic Acids Res. 2022;50(11):6116-6136. doi:10.1093/nar/gkac450
Das C, Gadad SS, Kundu TK. Human Positive Coactivator 4 Controls Heterochromatinization and Silencing of Neural Gene Expression by Interacting with REST/NRSF and CoREST. J Mol Biol. 2010;397(1):1-12. doi:10.1016/j.jmb.2009.12.058
Sikder S, Kumari S, Mustafi P, et al. Nonhistone human chromatin protein PC4 is critical for genomic integrity and negatively regulates autophagy. FEBS J. 2019;286(22):4422-4442. doi:10.1111/febs.14952
Batta K, Yokokawa M, Takeyasu K, et al. Human Transcriptional Coactivator PC4 Stimulates DNA End Joining and Activates DSB Repair Activity. J Mol Biol. 2009;385(3):788-799. doi:10.1016/j.jmb.2008.11.008
Swaminathan A, Delage H, Chatterjee S, et al. Transcriptional coactivator and chromatin protein PC4 is involved in hippocampal neurogenesis and spatial memory extinction. J Biol Chem. 2016;291(39):20303-20314. doi:10.1074/jbc.M116.744169
Ochiai K, Yamaoka M, Swaminathan A, et al. Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4. Cell Rep. 2020;33(12). doi:10.1016/j.celrep.2020.108517
Sikder S and Agrawal A et al. KAT5 Acetylates Human Chromatin Protein PC4 to promote DNA Repair. bioRxiv. 2024. doi: https://doi.org/10.1101/2024.01.12.575390)
Sikder S., Kumari S., Kumar M., et al. Chromatin protein PC4 is downregulated in breast cancer to promote disease progression: Implications of miR-29a. Oncotarget. 2019; 10: 6855-6869. Retrieved from https://www.oncotarget.com/article/27325/text/.
II. The p53 regulates epigenetic enzymes: implications in oral cancer and adipogenesis
1. Kishore AH, Batta K, Das C, et al. p53 regulates its own activator: transcriptional co-activator PC4, a new p53-responsive gene. Biochem J. 2007;406(3):437-444. doi:10.1042/BJ20070390
2. Banerjee S, Kumar BR, Kundu TK. General transcriptional coactivator PC4 activates p53 function. Mol Cell Biol. 2004;24(5):2052-2062. doi:10.1128/MCB.24.5.2052-2062.2004
3. Batta K, Kundu TK. Activation of p53 function by human transcriptional coactivator PC4: role of protein-protein interaction, DNA bending, and posttranslational modifications [published correction appears in Mol Cell Biol. 2020 Sep 14;40(19):e00364-20. doi: 10.1128/MCB.00364-20]. Mol Cell Biol. 2007;27(21):7603-7614. doi:10.1128/MCB.01064-07
4. Kaypee S, Sahadevan SA, Patil S, et al. Mutant and Wild-Type Tumor Suppressor p53 Induces p300 Autoacetylation. iScience. 2018;4:260-272. doi:10.1016/j.isci.2018.06.002
5. Behera AK, Bhattacharya A, Vasudevan M, et al. p53 mediated regulation of coactivator associated arginine methyltransferase 1 (CARM1) expression is critical for suppression of adipogenesis. FEBS J. 2018;285(9):1730-1744. doi:10.1111/febs.14440
6. Ghosh R, Kaypee S, Shasmal M, et al. Tumor Suppressor p53-Mediated Structural Reorganization of the Transcriptional Coactivator p300. Biochemistry. 2019;58(32):3434-3443. doi:10.1021/acs.biochem.9b00333
7. Ghosh A, Singh S, Mallick TR, et al. Comprehensive genomic and digital pathology profiling of tobacco-chewer female oral cancer patients simultaneously with integration of single-cell datasets identifies clinically actionable patient subgroups. Clin Transl Med. 2025;15(7):e70386. doi:10.1002/ctm2.70386
8. Singh S, Kumar M, Kumar S, et al. The cancer-associated, gain-of-function TP53 variant P152Lp53 activates multiple signaling pathways implicated in tumorigenesis. J Biol Chem. 2019;294(38):14081-14095. doi:10.1074/jbc.RA118.007265
III. A nucleolar protein activates RNA polymerase II driven transcription: implications in oral cancer
1. Shandilya J, Swaminathan V, Gadad SS, et al. Acetylated NPM1 localizes in the nucleoplasm and regulates transcriptional activation of genes implicated in oral cancer manifestation. Mol Cell Biol. 2009;29(18):5115-5127. doi:10.1128/MCB.01969-08
2. Swaminathan V, Kishore AH, Febitha KK, et al. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol. 2005;25(17):7534-7545. doi:10.1128/MCB.25.17.7534-7545.2005
3. Gadad SS, Shandilya J, Swaminathan V, et al. Histone chaperone as coactivator of chromatin transcription: role of acetylation. Methods Mol Biol. 2009;523:263-278. doi:10.1007/978-1-59745-190-1_18
4. Senapati P, Dey S, Sudarshan D, et al. Oncogene c-fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation. FEBS J. 2018;285(18):3503-3524. doi:10.1111/febs.14625
5. Senapati P, Bhattacharya A, Das S, et al. Histone Chaperone Nucleophosmin Regulates Transcription of Key Genes Involved in Oral Tumorigenesis. Mol Cell Biol. 2022;42(2):e0066920. doi:10.1128/MCB.00669-20
IV. Epigenetic landscape of oral cancer
1. Behera AK, Kumar M, Shanmugam MK, et al. Functional interplay between YY1 and CARM1 promotes oral carcinogenesis. Oncotarget. 2019;10(38):3709-3724. Published 2019 Jun 4. doi:10.18632/oncotarget.26984
V. Small molecule modulators of epigenetic enzymes
A) Small molecule modulators of chromatin modifying enzymes to elucidate differentiation pathways:
1. Modak R, Basha J, Bharathy N, et al. Probing p300/CBP associated factor (PCAF)-dependent pathways with a small molecule inhibitor. ACS Chem Biol. 2013;8(6):1311-1323. doi:10.1021/cb4000597
2. Selvi BR, Swaminathan A, Maheshwari U, Nagabhushana A, Mishra RK, Kundu TK. CARM1 regulates astroglial lineage through transcriptional regulation of Nanog and posttranscriptional regulation by miR92a. Mol Biol Cell. 2015;26(2):316-326. doi:10.1091/mbc.E14-01-0019
3. Chatterjee S, Mizar P, Cassel R, et al. A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci. 2013;33(26):10698-10712. doi:10.1523/JNEUROSCI.5772-12.2013
4. Bharathy N, Suriyamurthy S, Rao VK, et al. P/CAF mediates PAX3-FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma. J Pathol. 2016;240(3):269-281. doi:10.1002/path.4773
5. Smitha, A. S., Akash Kumar Singh, Jaya Lakshmi PR, et al. p300/CBP KATs Are Critical for Maturation and Differentiation of Adult Neural Progenitors. ACS Chemical Biology (2024). doi/full/10.1021/acschembio.4c00465
6. Selvi, B Ruthrotha et al. “Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17.” The Journal of biological chemistry vol. 285,10 (2010): 7143-52. doi:10.1074/jbc.M109.063933
B) Inhibitors of KATs: potential therapeutic molecules:
1. Mantelingu K, Reddy BA, Swaminathan V, et al. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. Chem Biol. 2007;14(6):645-657. doi:10.1016/j.chembiol.2007.04.011
2. Arif M, Vedamurthy BM, Choudhari R, et al. Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A. Chem Biol. 2010;17(8):903-913. doi:10.1016/j.chembiol.2010.06.014
3. Selvi RB, Swaminathan A, Chatterjee S, et al. Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse `model. Oncotarget. 2015;6(41):43806-43818. doi:10.18632/oncotarget.6245
4. Sethi G, Chatterjee S, Rajendran P, et al. Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo. Mol Cancer. 2014;13:66. Published 2014 Mar 21. doi:10.1186/1476-4598-13-66
5. Balasubramanyam K, Altaf M, Varier RA, et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem. 2004;279(32):33716-33726. doi:10.1074/jbc.M402839200
C) Specific KAT activator: Implications in Neurological Disorders:
1. Selvi BR, Jagadeesan D, Suma BS, et al. Intrinsically fluorescent carbon nanospheres as a nuclear targeting vector: delivery of membrane-impermeable molecule to modulate gene expression in vivo. Nano Lett. 2008;8(10):3182-3188. doi:10.1021/nl801503m
2. Chatterjee S, Mizar P, Cassel R, et al. A Novel Activator of CBP/p300 Acetyltransferases Promotes Neurogenesis and Extends Memory Duration in Adult Mice. J Neurosci. 2013;26;33(26): 10698-712
3. Hutson TH, Kathe C, Palmisano I, et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Sci Transl Med. 2019;11(487):eaaw2064. doi:10.1126/scitranslmed.aaw2064
4. Chatterjee S, Cassel R, Schneider-Anthony A, et al. Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med. 2018;10(11):e8587. doi:10.15252/emmm.201708587
5. Singh AK, Neo SH, Liwang C, et al. Glucose derived carbon nanosphere (CSP) conjugated TTK21, an activator of the histone acetyltransferases CBP/p300, ameliorates amyloid-beta 1-42 induced deficits in plasticity and associativity in hippocampal CA1 pyramidal neurons. Aging Cell. 2022;21(9):e13675. doi:10.1111/acel.13675
6. Singh AK., Joshi I., Reddy N. M.N., et al. Epigenetic Modulation to perturb the SYNGAP1 Intellectual Disability (ID) that ameliorates synaptic and behavioral deficits. BioRxiv. 2024. doi:10.1101/2024.01.03.574003
7. Singh AK, Rai A, Joshi I, et al. Oral Administration of a Specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairs Spinal Cord Injury. ACS Chem Neurosci. 2024;15(15):2741-2755. doi:10.1021/acschemneuro.4c00124
D) Butyrylation meets adipogenesis - probed by p300 catalyzed acylation-specific small molecule inhibitor: Implication in anti-obesity therapy
1. Bhattacharya A, Chatterjee S, Bhaduri U, et al. Butyrylation Meets Adipogenesis-Probed by a p300-Catalyzed Acylation-Specific Small Molecule Inhibitor: Implication in Anti-obesity Therapy. J Med Chem. 2022;65(18):12273-12291. doi:10.1021/acs.jmedchem.2c00943
VI. Surface-Enhanced Raman Scattering (SERS): A Tool to Screen and Characterize Small Molecule Modulators of Enzymes
1. Mantelingu K, Kishore AH, Balasubramanyam K, et al. Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: probed by surface-enhanced Raman spectroscopy. J Phys Chem. 2007; B 111:4527–4534
2. Mantelingu K, Reddy BA, Swaminathan V, et al. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. Chem Biol. 2007;14:645–657
3. Karthigeyan D, Siddhanta S, Kishore AH, et al. SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool. Proc Natl Acad Sci U S A. 2014;111(29): 10416-21
4. Arif M, Karthigeyan D, Siddhanta S, et al. Analysis of protein acetyltransferase structure-function relation by surface-enhanced Raman scattering (SERS): a tool to screen and characterize small molecule modulators. Methods Mol Biol. 2013; 981: 239-61