Biology subjects

Abd-Rabbo, D.

Publications and source records attributed to Abd-Rabbo, D..

6 recordsLinked to original sources

bioRxiv2024

Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes

Type-II topoisomerases resolve topological stress in DNA through controlled double-strand breaks. While TOP2A is a chemotherapy target in proliferating cells, the ubiquitously expressed TOP2B is a potential off-target. Here we explore roles of TOP2B in mutagenesis by generating DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analysing these maps for driver mutations and mutational processes in 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants (SVs), especially at evolutionary conserved sites displaying high transcription and long-range chromatin interactions. TOP2B binding underlies SVs and hotspot mutations in cancer-driving genes such as TP53, MYC, FOXA1, and VHL, and many cis-regulatory elements. We show that the TOP2B-bound mutational hotspot at RMRP drives tumor initiation and growth in vivo. These data highlight TOP2B as a protector of the genome from topological challenges whose aberrant activity promotes driver and passenger mutations in cancer genomes.

cancer biology↗

bioRxiv2024

A Unified Atlas of T cell Glycophysiology

Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo. Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across multiple mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodelled in response to antigen-specific stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodelling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.

immunology↗

bioRxiv2023

Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control

CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (TTS) cells during cancer development is still unclear. We demonstrate that CD4 TTS cells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 TTS cells and previously defined exhaustion programs, CD4 TTS cell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 TTS cell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 TTS cells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTS cells to favor tumor progression.

cancer biology↗

bioRxiv2020

Functional and genetic determinants of mutation rate variability in regulatory elements of cancer genomes

BackgroundCancer genomes are shaped by mutational processes with complex spatial variation at multiple scales. Entire classes of regulatory elements are affected by local variations in mutation frequency. However, the underlying mutational mechanisms with functional and genetic determinants remain poorly understood. ResultsWe characterised the mutational landscape of 1.3 million gene regulatory and chromatin architectural elements in 2,419 whole cancer genomes with transcriptional and pathway activity, functional conservation and recurrent driver events. We developed RM2, a statistical model that quantifies mutational enrichment or depletion in classes of genomic elements through genetic, trinucleotide and megabase-scale effects. We report a map of localised mutational processes affecting CTCF binding sites, transcription start sites (TSS) and tissue-specific open-chromatin regions. We show that increased mutational frequency in TSSs correlates with mRNA abundance in most cancer types, while open-chromatin regions are generally enriched in mutations. We identified [~]10,000 CTCF binding sites with core DNA motifs and constitutive binding in 66 cell types that represent focal points of local mutagenesis. We detected site-specific mutational signatures, such as SBS40 in open-chromatin regions in prostate cancer and SBS17b in CTCF binding sites in gastrointestinal cancers. We also proposed candidate drivers of localised mutagenesis: BRAF mutations associate with mutational enrichments at CTCF binding sites in melanoma, and ARID1A mutations with TSS-specific mutations in pancreatic cancer. ConclusionsOur method and catalogue of localised mutational processes provide novel perspectives to cancer genome evolution, mutagenesis, DNA repair and driver discovery. Functional and genetic correlates of localised mutagenesis provide mechanistic hypotheses for future studies.

genomics↗

bioRxiv2018

Integrative pathway enrichment analysis of multivariate omics data

Multi-omics datasets quantify complementary aspects of molecular biology and thus pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple omics datasets using a statistical data fusion approach, rationalizes contributing evidence and highlights associated genes. We demonstrate its utility by analyzing coding and non-coding mutations from 2,583 whole cancer genomes, revealing frequently mutated hallmark pathways and a long tail of known and putative cancer driver genes. We also studied prognostic molecular pathways in breast cancer subtypes by integrating genomic and transcriptomic features of tumors and tumor-adjacent cells and found significant associations with immune response processes and anti-apoptotic signaling pathways. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.

bioinformatics↗

bioRxiv2017

A Yeast Global Genetic Screen Reveals that Metformin Induces an Iron Deficiency-Like State

We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins or other small molecules based on \"homomer dynamics\" Protein-fragment Complementation Assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health-span-affecting drugs, immunosuppressant rapamycin and type II diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatments of diabetes, cancers and other chronic diseases of aging.

systems biology↗