Biology subjects

Kabir, S.

Publications and source records attributed to Kabir, S..

7 recordsLinked to original sources

bioRxiv2026

Historical genomes reveal scale-dependent predictability of climate adaptation

Predicting evolution remains a central challenge in biology. Contemporary spatial patterns are increasingly used as space-for-time proxies to forecast evolutionary responses to environmental change, yet the reliability of such predictions--and whether it varies among biological scales--remains unclear. Using historical and contemporary genomes of the invasive weed Ambrosia artemisiifolia--spanning the species' native range, invasions on two continents and nearly two centuries--we show that genomically predicted flowering-time clines remained stable in the native range while introduced populations re-evolved them. Haploblocks--likely structural variants--were likewise temporally stable in the native range, and two showed striking parallel evolution across all three ranges. Climate-associated SNPs with the strongest contemporary clines showed the greatest temporal change, with limited and variable parallelism among introduced ranges. Together, these results suggest adaptive evolution is partly predictable even when individual genomic trajectories remain flexible and contingent, with predictability emerging most clearly at the level of polygenic traits and large structural variants.

evolutionary biology↗

bioRxiv2025

REV7 associates with ATRIP and inhibits ATR kinase activity

Integration of DNA replication with DNA repair, cell cycle progression, and other biological processes is crucial for preserving genome stability and fundamentally important for all life. Ataxia-telangiectasia mutated and RAD3-related (ATR) and its partner ATR-interacting protein (ATRIP) function as a critical proximal sensor and transducer of the DNA Damage Response (DDR). Several ATR substrates, including p53 and CHK1, are crucial for coordination of cell cycle phase transitions, transcription, and DNA repair when cells sustain DNA damage. While much is known about ATR activation mechanisms, it is less clear how ATR signaling is negatively regulated in cells. Here, we identify the DNA repair protein REV7 as a novel direct binding partner of ATRIP. We define a REV7-interaction motif in ATRIP, which when mutated abrogates the REV7-ATRIP interaction in vitro and in intact cells. Using in vitro kinase assays, we show that REV7 inhibits ATR-mediated phosphorylation of its substrates, including p53. Disruption of the REV7-ATRIP interaction also enhances phosphorylation of CHK1 at Ser317 (a known ATR target site) in intact cells. Taken together our results establish REV7 as a critical negative regulator of ATR signaling. REV7 has pleiotropic roles in multiple DDR pathways including Trans-Lesion Synthesis, DNA Double-Strand Break resection, and p53 stability and may play a central role in the integration of multiple genome maintenance pathways.

molecular biology↗

bioRxiv2024

Rapid parallel adaptation in distinct invasions of Ambrosia artemisiifolia is driven by large-effect structural variants

When introduced to multiple distinct ranges, invasive species provide a compelling natural experiment for understanding the repeatability of adaptation. Ambrosia artemisiifolia is an invasive, noxious weed and chief cause of hay fever. Leveraging over 400 whole-genome sequences spanning the native range in North America and two invasions in Europe and Australia, we inferred demographically distinct invasion histories on each continent. Despite substantial differences in genetic source and effective population size changes during introduction, scans of both local climate adaptation and divergence from the native range revealed genomic signatures of parallel adaptation between invasions. Disproportionately represented among these parallel signatures are 37 large haploblocks - indicators of structural variation - that cover almost 20% of the genome and exist as standing genetic variation in the native range. Many of these haploblocks are associated with traits important for adaptation to local climate, like size and the timing of flowering, and have rapidly reformed native range clines in invasive ranges. Others show extreme frequency divergence between ranges, consistent with a response to divergent selection on different continents. Our results demonstrate the key role of large-effect standing variants in rapid adaptation during range expansion, a pattern that is robust to diverse invasion histories.

genomics↗

bioRxiv2023

Functional Screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair

Homology Directed Repair (HDR) enables precise genome editing and holds great promise in the gene therapy field. However, the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we demonstrate the development of a functional, pooled screening platform utilizing an HDR-based readout to identify protein-based reagents that improve HDR outcomes in human hematopoietic stem and progenitor cells (HSPCs), a clinically relevant cell type for gene therapy. We leveraged this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, and we identified optimized i53 variants that enable new intermolecular bonds and robustly increase HDR. These variants specifically reduce insertion-deletion outcomes and also synergize with a DNAPK inhibitor to increase HDR rates. When applied at manufacturing scale, the incorporation of improved variants results in a significant increase in cells with at least one repaired allele and improved HDR in long-term HSPCs subpopulations, while not increasing off-target editing or gross chromosomal rearrangements. We anticipate the pooled screening platform will enable discovery of future gene editing reagents that improve HDR outcomes, such as the i53 variants reported here.

molecular biology↗

bioRxiv2022

An in vivo and in silico evaluation of the magical hepatoprotective potentialities of Gynura procumbens: a promising agent for combating hepatotoxicity

IntroductionLiver being the most important metabolic organ of the body performs a wide variety of vital functions. Hepatic cell injury occurs by the activation of reactive oxygen species (ROS) by CCl4, xenobiotics and other toxic substances generated through cytochrome P450 dependent step resulting from covalent bond formation with lipoproteins and nucleic acids. Observing the alarming state of hepatotoxic patients worldwide, different medicinal plants and their properties can be explored to combat against such free radical degermation of liver. This paper evaluates the antioxidant property of Gynura procumbens in both in silico and in an in vivo assay, and its hepatoprotective activity in CCl4 induced hepatotoxicity. Materials and MethodsGynura procumbens leaves were collected and extracted using 50% ethanol. Required chemicals (CCl4), standard drug (Silymarin) and blood serum analyzing kits were stocked. The in vivo tests were performed in 140 healthy Wister albino male rats under well controlled parameters dividing into 14 groups, strictly maintaining IEAC protocols. In silico molecular docking and ADMET studies were performed and the results were analyzed statistically. Results and discussionThe body weight increased significantly in CCl4 induced, G. procumbens administered hepatotoxic rats. The increase in SGPT, SGOT, ALP, creatinine, LFH, triglycerides, LDL, SOD, MDA, total cholesterol, DNA fragmentation ranges, {gamma}GT levels of CCl4 treated group was decreased by both standard drug Silymarin and G. procumbens leaf extract. On the other hand, G. procumbens increased HDL levels and displayed contrasting results in CAT level tests. Some results contradicted with the negative controlled group displaying varying efficacy between leaf extract and Silymarin. In the molecular docking analysis, G. procumbens phytoconstituents performed poorly against TGF-{beta}1 compared to the control drug Galunisertib while 26 phytoconstituents scored better than the control, bezafibrate against PPAR-. Flavonoids and phenolic compounds performed better than other constituents in providing hepatoprotective activity.

bioinformatics↗

bioRxiv2019

Genome editing to model and reverse a prevalent mutation associated with myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) cause the over-production of blood cells such as erythrocytes (polycythemia vera) or platelets (essential thrombocytosis). JAK2 V617F is the most prevalent somatic mutation in many MPNs, but previous modeling of this mutation in mice relied on transgenic overexpression and resulted in diverse phenotypes that were in some cases attributed to expression level. CRISPR-Cas9 engineering offers new possibilities to model and potentially cure genetically encoded disorders via precise modification of the endogenous locus in primary cells. Here we develop "scarless" Cas9-based reagents to create and reverse the JAK2 V617F mutation in an immortalized human erythroid progenitor cell line (HUDEP-2), CD34+ adult human hematopoietic stem and progenitor cells (HSPCs), and immunophenotypic long-term hematopoietic stem cells (LT-HSCs). We find no overt in vitro increase in proliferation associated with an endogenous JAK2 V617F allele, but co-culture with wild type cells unmasks a competitive growth advantage provided by the mutation. Acquisition of the V617F allele also promotes terminal differentiation of erythroid progenitors, even in the absence of hematopoietic cytokine signaling. Taken together, these data are consistent with the gradually progressive manifestation of MPNs and reveals that endogenously acquired JAK2 V617F mutations may yield more subtle phenotypes as compared to transgenic overexpression models.

cancer biology↗

bioRxiv2019

The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells

Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL is a frequent event in blood and solid cancers. Inhibitors targeting MCL1 are in clinical development, however many cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens that interrogate two drugs directly or indirectly targeting MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components particularly skewed the balance in favor of apoptosis when cells were challenged with an MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to MCL1 inhibitors exposes new drug targets and the potential to improve combination treatments.

cancer biology↗