Biology subjects

Chandna, S.

Publications and source records attributed to Chandna, S..

3 recordsLinked to original sources

bioRxiv2022

Sustained pigmentation causes DNA damage and invokes translesion polymerase Pol κ for repair in melanocytes

The pigment melanin protects skin cells from ultraviolet (UV) radiation induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases DNA damage, causes cell cycle arrest, and invokes translesion polymerase Pol {kappa} for DNA repair in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase, the key melanin synthesizing enzyme results in depigmented cells with low Pol {kappa} levels. However, silencing of Pol {kappa} in pigmenting cells results in unchecked proliferation despite the presence of damaged DNA, that could potentially lead to genome instability. Thereby, our results indicate Pol {kappa} to be a necessary evil to resolve melanin induced damage. Error-prone repair by Pol {kappa} in part explains the mutational landscape observed in human melanoma. Thus, our study illuminates a hitherto unknown dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis mediated via the Pol {kappa}-based low fidelity DNA repair response of melanocytes. Key HighlightsO_LISustained melanogenesis causes DNA damage in melanocytes C_LIO_LIMelanogenesis elicits replication stress and translesion repair by Pol {kappa} C_LIO_LIPol {kappa} resolves melanin-induced DNA damage and suppresses genome instability C_LIO_LIExpression of Pol {kappa} correlates with mutational load in human melanoma C_LI

cell biology↗

bioRxiv2021

Glycolytic inhibitor 2-Deoxy-D-glucose attenuates SARS-CoV-2 multiplication in host cells and weakens the infective potential of progeny virions

The COVID-19 pandemic is an ongoing public health emergency of international concern. While a lot of efforts are being invested in vaccinating the population, there is also an emergent requirement to find potential therapeutics to effectively counter this fast mutating SARS-CoV-2 virus-induced pathogenicity. Virus-infected host cells switch their metabolism to a more glycolytic phenotype. This switch induced by the virus is needed for faster production of ATP and higher levels of anabolic intermediates, required for new virion synthesis and packaging. In this study, we used 2-Deoxy-D-glucose (2-DG) to target and inhibit the metabolic reprogramming induced by SARS-CoV-2 infection. Our results showed that virus infection induces glucose influx and glycolysis resulting in selective high accumulation of the fluorescent glucose/2-DG analogue, 2-NBDG in these cells. Subsequently, 2-DG inhibits glycolysis in infected cells thereby reducing the virus multiplication and alleviates the cells from virus induced cytopathic effect (CPE) and cell death. Herein, we demonstrate that the crucial Nglycosites (N331 and N343) of RBD in spike protein of progeny virions produced from 2-DG treated cells were found unglycosylated and defective with compromised infectivity potential. In line with earlier reported observations, our study also showed that 2-DG mediated metabolic inhibiton can attenuate SARS-COV-2 multiplication. In addition, mechanistic study revealed that the inhibition of SARS-COV-2 multiplication is attributed to 2-DG induced un-glycosylation of spike protein. Our findings strengthen the notion that 2-DG effectively inhibits SARS-CoV-2 multiplication. Therefore, based on its previous human trials in different types of Cancer and Herpes patients, it could be a potential molecule to study in COVID-19 patients.

cell biology↗

bioRxiv2021

Inference of tissue relative proportions of the breast epithelial cell types luminal progenitor, basal, and luminal mature

Single-Cell Analysis has revolutionised genomic science in recent years. However, due to cost and other practical considerations, single-cell analyses are impossible for studies based on medium or large patient cohorts. For example, a single-cell analysis usually costs thousands of euros for one tissue sample from one volunteer, meaning that typical studies using single-cell analyses are based on very few individuals. While single-cell genomic data can be used to examine the phenotype of individual cells, cell-type deconvolution methods are required to track the quantities of these cells in bulk-tissue genomic data. Hormone receptor negative breast cancers are highly aggressive, and are thought to originate from a subtype of epithelial cells called the luminal progenitor. In this paper, we show how to quantify the number of luminal progenitor cells as well as other epithelial subtypes in breast tissue samples using DNA and RNA based measurements. We find elevated levels of cells which resemble these hormone receptor negative luminal progenitor cells in breast tumour biopsies of hormone receptor negative cancers, as well as in healthy breast tissue samples from BRCA1 (FANCS) mutation carriers. We also find that breast tumours from carriers of heterozygous mutations in non-BRCA Fanconi Anaemia pathway genes are much more likely to be hormone receptor negative. These findings have implications for understanding hormone receptor negative breast cancers, and for breast cancer screening in carriers of heterozygous mutations of Fanconi Anaemia pathway genes.

bioinformatics↗