Biology subjects

Vaibhav, V.

Publications and source records attributed to Vaibhav, V..

4 recordsLinked to original sources

bioRxiv2026

Pre-existing levels of pro-survival proteins and induction of BCL-XL dictate cell fate after p53 activation

TP53 (also called TRP53 or p53) is a critical tumour suppressor that prevents cancer development by inducing a transcriptional program which can lead to diverse cellular responses, most prominently, cell proliferation arrest/senescence with survival of cells or cell death by apoptosis. Why distinct cell types undergo different outcomes after p53 activation remains unclear. Using integrated RNA-sequencing, proteomic and functional analyses across a diverse range of murine primary cell types, we demonstrate that cell fate is governed by the balance between pro-survival BCL-2 and pro-apoptotic BH3-only proteins. Cells resistant to apoptosis displays a higher starting ratio of pro-survival BCL-2 to pro-apoptotic BH3-only proteins, along with transcriptional upregulation of the pro-survival gene Bcl2l1, encoding BCL-XL. This control of cell fate is also seen in human wild-type p53 cancer cell lines. These findings reveal the mechanism for understanding p53-driven cell fate decisions, suggest therapeutic strategies to shift p53-induced cell proliferation arrest/senescence toward apoptotic cell death and allowed generation of an RNAseq data-based predictor of outcome for cancer cells after p53 activation.

cancer biology↗

bioRxiv2025

Global analysis of cancer cell responses to USP9X inhibition

The ubiquitin specific protease (USP) enzyme USP9X is amongst the best studied human deubiquitinases (DUBs), with a myriad of described targets and cellular roles. In cancer, USP9X has been touted as both an oncogene and a tumour suppressor in different contexts, which has confounded the field and questioned its viability as a cancer target. We here describe WEHI-092, a novel piperazine-based USP9X specific small molecule inhibitor and map its binding site to a unique region in the USP9X fingers subdomain, distinct from known DUB inhibitor binding sites. Using proteomics and ubiquitinomics, we show that USP9X has a distinct set of substrates compared to USP7 indicating remarkable DUB target specificity, yet the substrate profile of USP9X varies significantly across cancer cell lines. Interestingly, we reveal a core set of 17 proteins commonly regulated by USP9X in most or all cell lines, which we consider as proximal biomarkers for USP9X inhibition. Consistent with our proteomic analyses, we show that WEHI-092 treatment arrests cells in metaphase without inducing cell death, which may account for growth suppression seen in long-term clonogenic assays in most cancer cell lines, and positions USP9X inhibitors as a new potential class of selective mitotic poisons.

cell biology↗

bioRxiv2025

Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons

Huntingtons Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature-based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on the growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.

cell biology↗

bioRxiv2024

MORC2 phosphorylation fine tunes its DNA compaction activity

Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.

molecular biology↗