https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/8 2026-04-03T13:39:11Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1632 Title: Hydrophobicity of Cholic Acid-Derived Amphiphiles Dictates the Antimicrobial Specificity Authors: Siddhi, Gupta; Amit, Arora; Varsha, Saini,; Devashish, Mehta; Mehak Zahoor, Khan; Deepak K., Mishra; Prabhu Srinivas, Yavvari; Archana, Singh; Sonu Kumar, Gupta; Aasheesh, Srivastava; Yashwant, Kumar; Vikas, Verma; Vinay K., Nandicoori Abstract: The unique structural components of cell membranes of Gram-positive bacteria, Gram-negative bacteria, and mycobacteria provide an excellent therapeutic target for developing highly specific antimicrobials. Here, we report the synthesis of nine cholic acid (CA)-derived amphiphiles, where three hydroxyl groups of CA were tethered to dimethylamino pyridine and the C24-carboxyl group was conjugated with different alkyl chains. Structure−activity investigations revealed that amphiphile 1 harboring a methyl group has antimicrobial activity against mycobacterial species. On the other hand, amphiphile 7 containing an octyl chain was selective against Gram-positive and Gram-negative bacilli. Biochemical assays confirmed the selective membrane permeabilization abilities of amphiphiles 1 and 7. Importantly, we demonstrate the selective actions of amphiphiles in clearing biofilms, intracellular bacteria, and wound infections. Therefore, for the first time, we show that the unique structural features of CA- derived amphiphiles dictate selective activity against specific bacterial species. 2022-01-01T00:00:00Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1631 Title: Whole-Exome Sequencing of Vitiligo Lesions Indicates Lower Burden of Somatic Variations: Implications in Risk for Nonmelanoma Skin Cancers Authors: Gupta, I; Shankrit, S; Narta, K; Ghazi, M; Grover, R; Ritika, R; Kar, HK; Menon, SM; Gupta, A; Yenamandra, VK; Singh, A; Mukerji, M; Mukhopadhyay, A; Rani, R; Gokhale, RS; Dash, D; Natarajan, VT Abstract: Genetic depigmentary conditions such as albinism with complete loss of epidermal pigmentation pose a higher risk for cutaneous malignancies (Lekalakala et al., 2015; Kromberg et al., 1989). By analogy, clinical management for photoprotection of the acquired depigmented skin in vitiligo is of serious concern. It is believed that vitiligo would pose a similar, elevated risk. Systematic evaluation of a large cohort of subjects with vitiligo indicated a decreased risk for both melanoma and nonmelanoma skin cancers (Hexsel et al., 2009; Kim et al., 2020; Paradisi et al., 2014; Rodrigues, 2017; Schallreuter et al., 2002; Teulings et al., 2013; Weng et al., 2021). Extrapolating from demographic studies, it is tempting to speculate that vitiligo could negatively influence either initiation or progression of cutaneous malignancies (Rodrigues, 2017). Given the autoimmune etiology that targets melanocyte destruction, protection against melanoma could be rationalized; however, similar protection from nonmelanoma skin cancer is perplexing. Therefore, these observations need to be substantiated with evidence at the tissue level. Recent advancements in genomics enable the mapping of the somatic variations that would act as a molecular correlate for cancer. In normal, seemingly healthy skin, deep sequencing of a selected panel of cancer-associated genes suggests a pervasive positive selection of somatic variations that provides valuable insights into the origin of somatic variations and map their progression to skin cancers 2023-01-01T00:00:00Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1578 Title: p53 regulates DREAM complex-mediated repression in a p21-independent manner Authors: Sengupta, Sagar; Agrawal, Ritu Abstract: The DREAM repressor complex regulates genes involved in the cell cycle and DNA repair, vital for maintaining genome stability. Although it mediates p53-driven repression through the canonical p53-p21-Rb axis, the potential for p53 to directly regulate DREAM targets independently of its transcriptional activity has not been explored. Here, we demonstrate that in asynchronously growing cells, p53 loss leads to greater de-repression of DREAM targets compared to p21 loss alone. Both wild-type and transactivation-deficient p53 mutants are capable of repressing DREAM targets, suggesting a transactivation-independent "non-canonical" repression mechanism. These p53 variants bind p130/p107, irrespective of their phosphorylation status, while cancer-associated p53 mutants disrupt DREAM complex function by sequestering E2F4. Re-ChIP analysis shows co-recruitment of p53 and E2F4 to known and newly identified DREAM target promoters, indicating direct repression of these targets by p53. These findings reveal a novel, transactivation-independent mechanism of p53-mediated repression, expanding our understanding of p53's tumor-suppressive functions and suggesting DREAM complex targeting as potential future avenues in cancer therapy. 2025-01-01T00:00:00Z https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/1575 Title: Phosphorylated BLM peptide acts as an agonist for DNA damage response Authors: Agrawal, Ritu; Agarwal, Himanshi; Mukherjee, Chetana; Chakraborty, Baishali; Sharma, Vandana; Tripathi, Vivek; Kumar, Nitin; Priya, Swati; Gupta, Nidhi; Jhingan, Gagan Deep; Bajaj, Avinash; Sengupta, Sagar Abstract: Upon exposure to ionizing irradiation, the MRE11-RAD50-NBS1 complex potentiates the recruitment of ATM (ataxia-telangiectasia mutated) kinase to the double-strand breaks. We show that the lack of BLM causes a decrease in the autophosphorylation of ATM in mice mammary glands, which have lost one or both copies of BLM. In isogenic human cells, the DNA damage response (DDR) pathway was dampened in the absence of BLM, which negatively affected the recruitment of DDR factors onto the chromatin, thereby indicating a direct role of BLM in augmenting DDR. Mechanistically, this was due to the BLM-dependent dissociation of inactive ATM dimers into active monomers. Fragmentation analysis of BLM followed by kinase assays revealed a 20-mer BLM peptide (91-110 aa), sufficient to enhance ATM-dependent p53 phosphorylation. ATM-mediated phosphorylation of BLM at Thr99 within BLM (91-110) peptide enhanced ATM kinase activity due to its interaction with NBS1 and causing ATM monomerization. Delivery of phosphomimetic T99E counterpart of BLM (91-110 aa) peptide led to ATM activation followed by restoration of the DDR even in the absence of ionizing irradiation (both in cells and in BLM knockout mice), indicating its role as a DDR agonist, which can be potentially used to prevent the initiation of neoplastic transformation. 2025-01-01T00:00:00Z