Biology subjects

Ghazi, M.

Publications and source records attributed to Ghazi, M..

3 recordsLinked to original sources

bioRxiv2022

Whole exome-sequencing of vitiligo lesions indicate lower burden of somatic variations: implications in risk for non-melanoma skin cancers

Mapping of somatic variations has enabled understanding the progression of clonal variations from healthy skin to cutaneous malignancies. Highlighting, the adaptive nature of pigmentation, germline mutations in albinism amplify skin cancer susceptibility. However, lower incidence of non-melanoma skin cancer among subjects with acquired depigmenting skin disorder vitiligo is enigmatic and a matter of longstanding debate. To address this, we performed high-coverage exome sequencing of matched non-lesional and lesional vitiligo skin along with whole blood to account for germline variations. Our analysis suggests lower burden of somatic cancer-associated variations in exposed depigmented lesional skin compared to the non-lesional skin. A detailed investigation of vitiligo skin transcriptome reveals elevation of DNA repair and cell-proliferation pathways. Validation by comet-assay for DNA damage and cell cycle analysis of epidermal cells suggest undamaged DNA in vitiligo lesions that could be attributed to higher proliferation-coupled repair. Endorsing this, UV-signature variations are not prominent, instead SBS5 associated with endogenous mutational processes is conspicuous in both the vitiligo tissues. Our systematic pilot study indicates lower somatic mutation burden in vitiligo skin and supports the earlier demographic observation on lower risk of non-melanoma skin cancer in vitiligo subjects, providing an opportunity to learn strategies for cancer prevention from vitiligo. Brief SummaryVitiligo skin harbors decreased somatic variation burden in cancer-associated genes and a concomitant augmentation in DNA repair response, explaining the lower incidence of cutaneous malignancies.

genomics↗

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

Baseline cell proliferation rates and response to UV differ in Lymphoblastoid Cell Lines derived from healthy individuals of extreme constitution types

Differences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate the molecular players for individualized and early interventions. Functional studies in Lymphoblastoid Cell Line (LCL) model of phenotypically well characterized healthy individuals can help deconvolute and validate these molecular mechanisms. We developed LCLs from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV was studied in these LCLs. We observed significant differences in cell proliferation rates between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one fast growing group (Vata) shows higher cell death but recovers its numbers due to inherent higher rates of proliferation. The baseline differences in cell proliferation are key to understanding the survival of cells in UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitutions types but can also help set priors during designing an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes amongst healthy individuals that have implications in precision medicine.

cell biology↗