Biology subjects

Lockett, S.

Publications and source records attributed to Lockett, S..

3 recordsLinked to original sources

bioRxiv2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNAs role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging. Significance StatementLamin A/C, a key structural component of the nuclear envelope, is frequently lost or mutated in cancer, laminopathies, and aging-related disorders. Lamin A/C loss is associated with genomic instability, but the underlying mechanisms remain incompletely understood. We demonstrate that LMNA loss drives genomic instability by promoting R-loop accumulation through disrupted nuclear pore dynamics and impaired RNA export. These findings reveal a previously unrecognized link between LMNA loss, nuclear envelope dysfunction, and genome instability. Targeting this pathway could help mitigate genomic instability in aging and laminopathies, while leveraging R-loop accumulation may enhance the efficacy of DNA-damaging therapies in cancer.

cancer biology↗

bioRxiv2022

CK2 signaling from TOLLIP-dependent perinuclear endosomes is an essential feature of KRAS mutant cancers

Oncogenic RAS induces perinuclear translocation of the effector kinases ERK and CK2 and their scaffold, KSR1, forming endosomal signaling hubs termed perinuclear signaling centers (PSCs). PSCs are present in all cancer cell lines and tissues examined, suggesting that subcellular compartmentalization of oncogenic kinases drives tumorigenesis. However, the mechanism of perinuclear targeting, whether this location affects kinase substrate specificity, and the importance of PSCs in cancer are unclear. Here we show that the endosomal adaptor, TOLLIP, specifically tethers RAB11A+ signaling endosomes containing CK2 and KSR1 to the perinuclear ER. A predicted {beta}-hairpin fold in TOLLIP mediates binding to the KSR1 CA5 pseudo-kinase domain, recruiting CK2/KSR1 complexes to perinuclear endosomes. TOLLIP is essential for proliferation/survival of tumor cells carrying KRAS and NRAS mutations but not HRAS, BRAF, ERBB or PTEN lesions, or non-transformed cells. KRasG12D-induced lung lesions in Tollip-/- mice displayed reduced numbers of carcinomatous lesions, implicating TOLLIP in malignant progression. TOLLIP-dependent perinuclear CK2 was shown to phosphorylate discrete substrates, including proteins involved in translation and ribosome biogenesis such as RIOK1. Thus, TOLLIP is a key RAS pathway signaling adaptor in K/NRAS tumors whose inhibition is a specific vulnerability of these cancers.

cancer biology↗

bioRxiv2022

3'UTR-directed, kinase proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells

C/EBP{beta} is a potent regulator of oncogene-induced senescence (OIS) and the SASP. C/EBP{beta} is post-translationally activated in OIS cells by the effector kinases ERK1/2 and CK2. However, in tumor cells C/EBP{beta} activation is suppressed by its 3UTR. 3'UTR regulation of protein activity (UPA) requires a G/U-rich element (GRE) and its cognate binding protein, HuR. These components segregate CEBPB transcripts away from a perinuclear compartment harboring ERK1/2 and CK2, restricting C/EBP{beta} from its activating kinases. We report here that the mRNA decay proteins UPF1 and Staufen1/2 are essential UPA factors enriched within the perinuclear cytoplasm. STAU1/2 and UPF1 overlap with CK2 on perinuclear signaling endosomes where they promote localized CEBPB mRNA decay. UPF1 or STAU1/2 depletion in tumor cells increased CEBPB transcripts adjacent to CK2 foci, coinciding with C/EBP{beta} activation and senescence. The GRE and an adjacent STAU binding site independently suppress C/EBP{beta}-mediated senescence, while a distinct 3UTR region inhibits its SASP-inducing activity. KrasG12D-driven lung tumors in mice carrying a Cebpb GRE deletion rarely progressed to malignant adenocarcinomas, demonstrating the importance of UPA to enable tumor progression in vivo. Thus, kinase-proximal mRNA decay is a novel mechanism that inhibits C/EBP{beta} activation in tumor cells to facilitate senescence bypass.

cancer biology↗