Biology subjects

Nandi, S. P.

Publications and source records attributed to Nandi, S. P..

6 recordsLinked to original sources

bioRxiv2025

The DREAM complex links somatic mutation, lifespan, and disease

The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM activity and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM activity have decreased mutation rates. Second, DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM activity in Alzheimers patients predicts late disease onset and decreased risk for severe neuropathology. Finally, we show DREAM knockout protects against mutation accumulation in vivo, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in brains of mice. These findings position DREAM as a key regulator of aging.

bioinformatics↗

bioRxiv2025

Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis

Mutational processes are thought to act independently and additively. We challenge this view by demonstrating that DNA-adducting agents sensitize the genome to mutagenesis by APOBEC enzymes. A model tobacco carcinogen (NQO) triggers a 100-fold increase in APOBEC3B- catalyzed signature mutations and elevates oral carcinoma levels in vivo. A hallmark of this unidirectional synergy is strand-coordinated pairs of APOBEC signature mutations within 32nt of each other (didyma). Biochemical experiments show that APOBEC3B can catalyze didyma formation, and genetic studies demonstrate requirements for APOBEC3B and functional nucleotide excision repair (XPA in human cells and Rad14 in yeast). Analyses of lung and head & neck cancers show that APOBEC mutagenesis and didyma are elevated in tumors from smokers compared to non-smokers. Additional tumor types with links to DNA-adducting agents also exhibit didyma. These studies support a model in which DNA-adducting carcinogens activate nucleotide excision repair and amplify mutagenesis by APOBEC enzymes in cancer.

cancer biology↗

bioRxiv2024

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK

Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in [~]180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.

genomics↗

bioRxiv2024

Accelerated Hematopoietic Stem Cell Aging in Space

Stem cell aging is accelerated by macroenvironmental and microenvironmental stressors, including inflammation. Previously, the NASA Twins study revealed inflammatory cytokine upregulation, chromosomal alterations, and telomere changes suggestive of accelerated aging in low-Earth orbit (LEO). To investigate the effects of spaceflight on human hematopoietic stem and progenitor cell (HSPC) aging, the NASA-supported Integrated Space Stem Cell Orbital Research team performed four independent 30- to 45-day NASA missions with matched flight and ground HSPC nanobioreactors in automated CubeLabs. These experiments revealed loss of HSPC dormancy, reduced self-renewal capacity, mitochondrial DNA amplification, APOBEC3-induced C-to-T mutagenesis, reduced ADAR1p150 expression, and alterations in the expression of repetitive elements. These molecular changes are indicative of accelerated HSPC aging and pre-leukemia stem cell generation in space and may be predictable and preventable.

cancer biology↗

bioRxiv2023

Arsenic is a potent co-mutagen of ultraviolet light

Environmental co-exposures are widespread and are major contributors to carcinogenic mechanisms. Two well-established environmental agents causing skin cancer are ultraviolet radiation (UVR) and arsenic. Arsenic is a known co-carcinogen that enhances UVRs carcinogenicity. However, the mechanisms of arsenic co-carcinogenesis are not well understood. In this study, we utilized primary human keratinocytes and a hairless mouse model to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures revealed that, on its own, arsenic is neither mutagenic nor carcinogenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis as well as to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, was observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13 the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing genomics data from basal cell carcinomas and melanomas revealed that only a subset of human skin cancers harbor ID13 and, consistent with our experimental observations, these cancers exhibited an elevated UVR mutagenesis. Our results provide the first report of a unique mutational signature caused by a co-exposure to two environmental carcinogens and the first comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR. Importantly, our findings suggest that a large proportion of human skin cancers are not formed purely due to UVR exposure but rather due to a co-exposure of UVR and other co-mutagens such as arsenic.

cancer biology↗

bioRxiv2018

Nucleosome remodelling at origins of Global Genome-Nucleotide Excision Repair occurs at the boundaries of higher-order chromatin structure

Repair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in chromatin remains largely unknown. We recently demonstrated that Global Genome Nucleotide Excision Repair (GG-NER) in chromatin is organized into domains around open reading frames. Here, we identify these domains, and by examining DNA damage-induced changes in the linear structure of nucleosomes, we demonstrate how chromatin remodeling is initiated during repair. In undamaged cells, we show that the GG-NER complex occupies chromatin at nucleosome free regions of specific gene promoters. This establishes the nucleosome structure at these genomic locations, which we refer to as GG-NER complex binding sites (GCBSs). We demonstrate that these sites are frequently located at genomic boundaries that delineate chromasomally interacting domains (CIDs). These boundaries define domains of higher-order nucleosome-nucleosome interaction. We show that efficient repair of DNA damage in chromatin is initiated following disruption of H2A.Z-containing nucleosomes adjacent to GCBSs by the GG-NER complex.

genomics↗