Biology subjects

Leclair, N. K.

Publications and source records attributed to Leclair, N. K..

4 recordsLinked to original sources

bioRxiv2026

Splicing of ultraconserved poison exons controls mitotic fidelity and stem cell viability

SR proteins are essential splicing regulators whose expression is controlled in part through poison exons (PEs) -- ultraconserved non-coding exons that trigger nonsense-mediated decay -- yet the biological functions of these elements remain undefined. Here, we show that homozygous deletion of SRSF3-PE or TRA2{beta}-PE is selected against in mouse embryos and human induced pluripotent stem cells (iPSCs), and that conditional PE deletion causes apoptotic death in iPSCs but is tolerated in post-mitotic neurons, revealing a proliferative-state-specific requirement. Mechanistically, PE deletion elevates SR protein levels, triggers widespread splicing dysregulation, and disrupts the correct splicing of a mitotic gene network associated with spindle defects and mitotic errors. These findings establish ultraconserved poison exons as essential regulators of mitotic splicing fidelity and stem cell viability.

molecular biology↗

bioRxiv2025

Intron retention regulates STAT2 function and predicts immunotherapy response in lung cancer

Immunotherapy benefits only a subset of lung cancer patients, and the molecular determinants of variable outcomes remain unclear. Using long-read RNA-sequencing we mapped the landscape of alternative RNA splicing in human primary lung adenocarcinomas. We identified over 180,000 full-length mRNA isoforms, more than half of which were novel and many of which occurred in immune-related genes, particularly within the type I interferon response pathway. We discovered retained introns in the STAT2 gene that produce altered protein isoforms that regulate immune signaling and interferon responses. Furthermore, STAT2 intron retention levels predicted patient responses to checkpoint inhibitors. These findings position alternative splicing as a key regulator of tumor immune responses and reveal mRNA splicing alterations as potential biomarkers to identify patients who might respond to cancer immunotherapy.

immunology↗

bioRxiv2021

MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors

MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, a hallmark of cancer, but the mechanistic links between MYC and the splicing machinery remain underexplored. Here, we identify a network of splicing factors (SFs) co-expressed as SF-modules in MYC-active breast tumors. Of these, one is a pan-cancer SF-module, correlating with MYC-activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module is sufficient to induce splicing events that are also MYC-regulated in patient tumors and to increase organoid size and invasiveness, while its knockdown decreases organoid size. Finally, we uncover a pan-cancer splicing signature of MYC activity which correlates with survival in multiple tumor types. Our findings provide insight into the mechanisms and function of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors.

cancer biology↗

bioRxiv2020

The actin nucleation factors JMY and WHAMM enable a rapid p53-dependent pathway of apoptosis

The actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two, JMY and WHAMM, are required for rapid apoptotic responses. JMY and WHAMM enable p53-dependent cell death by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the small G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally plays a key role in cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD. Author SummaryThe actin cytoskeleton is a collection of protein polymers that assemble and disassemble within cells at specific times and locations. Cytoskeletal regulators called nucleation-promoting factors ensure that actin polymerizes when and where it is needed, and many of these factors are members of the Wiskott-Aldrich Syndrome Protein (WASP) family. Humans express 8 WASP-family proteins, but whether the different factors function in programmed cell death pathways is not well understood. In this study, we explored roles for each WASP-family member in apoptosis and found that a subfamily consisting of JMY and WHAMM are critical for a rapid pathway of cell death. Furthermore, the loss of JMY results in changes in gene expression, including a dramatic upregulation of the small G-protein RhoD, which appears to be crucial for cell survival. Collectively, our results point to the importance of JMY and WHAMM in driving intrinsic cell death responses plus a distinct function for RhoD in maintaining cell viability.

cancer biology↗