Biology subjects

Abbas, T.

Publications and source records attributed to Abbas, T..

7 recordsLinked to original sources

bioRxiv2026

FAST BOLD FMRI REVEALS THE SPATIOTEMPORAL COMPLEXITY OF NEUROVASCULAR COUPLING ALTERATIONS IN CEREBRAL SMALL VESSEL DISEASE

Recent advances in neurophysiology highlighted the potential of high temporal resolution in Blood-Oxygen Level Dependent (BOLD) functional MRI (fMRI), although it is not yet standard practice. We demonstrated that fast BOLD fMRI can detect single-subject, single-stimulus visually evoked responses to brief stimuli at 3T. We used fast fMRI in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a genetic form of cerebral small vessel disease (cSVD). Using 2- and 10-second visual stimuli, we probed different neurovascular coupling regimes and showed that different regions of interest detect different facets of vascular dynamics. CADASIL patients showed significant changes in the amplitude and timing of the BOLD response, indicating early-age neurovascular impairment unrelated to anatomical lesions, and providing strong discriminative and generalization performance. These findings resolve prior inconsistencies in fMRI studies of CADASIL, supporting the use of fast fMRI to develop non-invasive biomarkers for cSVD and other neurodegenerative disorders.

neuroscience↗

bioRxiv2024

Break-induced replication drives large-scale genomic amplifications in cancer cells

DNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies1-3. Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection4-11. Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR.

cancer biology↗

bioRxiv2022

Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells

The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergentresistant fraction within the nucleus, which is reminiscent of how inhibitors such as Talazoparib affect PARP1 fractionation. Because PARP7 is expressed in AR negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer. SignificanceRBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically-used PARP1 inhibitors.

cancer biology↗

bioRxiv2020

Intra-host variability in global SARS-CoV-2 genomes as signatures of RNA editing: implications in viral and host response outcomes

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying Variants Of Concern (VOC). Besides, viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host Single Nucleotide Variations (iSNVs). Analysing 1, 347 samples collected till June 2020, we recorded 18, 146 iSNV sites throughout the SARS-CoV-2 genome. Both, mutations in RdRp as well as APOBEC and ADAR mediated RNA editing seem to contribute to the differential prevalence of iSNVs in hosts. Noteworthy, 41% of all unique iSNVs were reported as SNVs by 30th September 2020 in samples submitted to GISAID, which increased to [~]80% by 30th June 2021. Following this, analysis of another set of 1, 798 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) variations appeared as iSNVs before getting fixed in the population. We also observe hyper-editing events at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/417519v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@12b6ac2org.highwire.dtl.DTLVardef@16df897org.highwire.dtl.DTLVardef@dbbec2org.highwire.dtl.DTLVardef@c8de14_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2020

EccDNA formation is dependent on MMEJ, repressed by c-NHEJ pathway, and stimulated by DNA double-strand break

Extrachromosomal circular DNAs (eccDNA) are widespread in normal and cancer cells and are known to amplify oncogenic genes. However, the mechanisms that form eccDNA have never been fully elucidated due to the complex interactions of DNA repair pathways and lack of a method to quantify eccDNA abundance. Through the development of a sensitive and quantitative assay for eccDNA we show that the formation of eccDNA is through resection dependent repair of double-strand DNA breaks, especially micro-homology mediated end joining, and through mismatch repair. The most significant decreases in eccDNA levels occurred in cells lacking PARP1, POLQ, NBS1, RAD54, and FAN1. Further, a significant increase in eccDNA occurred in cells lacking c-NHEJ proteins DNA-PKcs, XRCC4, XLF, LIG4 and 53BP1. This suggests that when alt-NHEJ pathways are utilized to repair DNA breaks by necessity, the formation of eccDNA is increased. Induced and site-directed double-strand DNA breaks increase eccDNA formation, even from a single break. Additionally, we find that eccDNA levels accumulate as cells undergo replication in S-phase and that levels of eccDNA are decreased if DNA synthesis is prevented. Together, these results show that the bulk of eccDNA form by resection based alt-NHEJ pathways, especially during DNA replication and the repair of double-strand breaks.

cancer biology↗

bioRxiv2020

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

Ionizing radiation-induced DSBs are repaired primarily by the Non-Homologous End Joining (NHEJ) pathway, but the details of how this is regulated in different chromatin contexts are far from understood. We have discovered a novel response to DSBs that promotes NHEJ selectively in euchromatin, based on a novel interaction between the EMT-inducing transcriptional repressor ZEB1, and the well-studied NHEJ-promoting DNA repair factor 53BP1. Using a number of approaches, we have discovered that the ZEB1-53BP1 association is amplified following exposure of cells to IR and that they co-localize at IR-induced foci (IRIF). Depletion of ZEB1 enhances radio-sensitivity and increases IR-induced chromosomal aberrations in an ATM-independent manner. The very rapid recruitment-within 2 seconds-of ZEB1 to euchromatic DSBs is like-wise ATM-independent, but DNA-PK-dependent and is required for subsequent recruitment of 53BP1. ZEB1 promotes NHEJ and inhibits HR through its homeodomain by inducing 53BP1-permissive, pro-NHEJ/anti-HR chromatin modifications. Lastly, depletion of ZEB1 increases hyper-resection at DSBs and inhibits physiological DSB repair. These results support the argument that ZEB1 plays an essential role in DSB repair in euchromatin by establishing a 53BP1-permissive/pro-NHEJ chromatin environment.

cancer biology↗

bioRxiv2020

Genetic differences between extreme and composite constitution types from whole exome sequences reveal actionable variations

Personalized medicine relies on successful identification of genome-wide variations that governs inter-individual differences in phenotypes and system level outcomes. In Ayurveda, assessment of composite constitution types "Prakriti" forms the basis for risk stratification, predicting health and disease trajectories and personalized recommendations. Here, we report a novel method for identifying pleiotropic genes and variants that associate with healthy individuals of three extreme and contrasting "Prakriti" constitutions through exome sequencing and state-of-the-art computational methods. Exome Seq of three extreme Prakriti types from 108 healthy individuals 54 each from genetically homogeneous populations of North India (NI, Discovery cohort) and Western India (VADU, Replication cohort) were evaluated. Fishers Exact Test was applied between Prakriti types in both cohorts and further permutation based p-value was used for selection of exonic variants. To investigate the effect of sample size per genetic association test, we performed power analysis. Functional impact of differentiating genes and variations were inferred using diverse resources -Toppfun, GTEx, GWAS, PheWAS, UK Biobank and mouse knockdown/knockout phenotype (MGI). We also applied supervised machine learning approach to evaluate the association of exonic variants with multisystem phenotypes of Prakriti. Our targeted investigation into exome sequencing from NI (discovery) and VADU (validation) cohorts datasets provide ~7,000 differentiating SNPs. Closer inspection further identified a subset of SNPs (2407 (NI) and 2393 (VADU)), that mapped to an overlapping set of 1181 genes. This set can robustly stratify the Prakriti groups into three distinct clusters with distinct gene ontological (GO) enrichments. Functional analysis further strengthens the potential pleiotropic effects of these differentiating genes/variants and multisystem phenotypic consequences. Replicated SNPs map to some very prominent genes like FIG4, EDNRA, ANKLE1, BCKDHA, ATP5SL, EXOCS5, IFIT5, ZNF502, PNPLA3 and IL6R. Lastly, multivariate analysis using random forest uncovered rs7244213 within urea transporter SLC14A2, that associate with an ensemble of features linked to distinct constitutions. Our results reinforce the concept of integration of Prakriti based deep phenotypes for risk stratification of healthy individuals and provides markers for early actionable interventions.

genomics↗