Blackmer, J. | Search bioRxiv

bioRxiv2025

Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification

Amplified centrosome number causes genomic instability, most severely through division into more than two aneuploid daughter cells (multipolar mitosis). Several mechanisms that suppress multipolar division have been uncovered, yet mechanisms that favor viable multipolar division are poorly understood. To uncover factors that promote viability in cells with frequent centrosome amplification and multipolar division, we conducted an unbiased Drosophila genetic screen. In 642 mutagenized lines, we exploited the ability of intestinal papillar cells to form and function despite multipolar divisions. Our top hit is an unnamed gene, CG3168. We name this gene synaptic vesicle glycoprotein 2, reflecting homology to human Synaptic Vesicle Glycoprotein 2 (SV2) proteins. GFP-tagged SV2 localizes to the plasma membrane. In cells with amplified centrosomes, SV2 positions membrane-adjacent centrosomes, which prevents severe errors in chromosome alignment and segregation. Our results uncover membrane-based multipolar division regulation and reveal a novel vulnerability in cells with common cancer properties.

cell biology↗

bioRxiv2023

p53 and RB Cooperate to Suppress Transposable Elements

Accumulating data suggest that the long interspersed nuclear element 1 (LINE1), a major class of transposable elements, can promote tumorigenesis by causing deletions of tumor suppressor genes, amplifications of oncogenes, and chromosomal translocations(1). LINE1 and other transposable elements such as short interspersed nuclear elements (SINEs) can be activated during cancer development. Aberrant transposon expression has been correlated with loss of p53, however, how the loss of p53 or other tumor suppressors leads to activation of transposons during tumorigenesis remains to be fully understood. Here, we investigate the link between loss of the p53 and RB tumor suppressors and derepression of transposable elements. We observe that loss of p53 and RB in mouse embryonic fibroblasts leads to epigenetic changes, such as loss of DNA and histone methylation, which correlate with marked upregulation of LINE and SINE transposable elements. These results suggest that p53 and RB may utilize epigenetic mechanisms that work in tandem to suppress transposons, which may contribute to tumor suppression. SignificanceThe two most commonly mutated genes in human cancer are p53 and the retinoblastoma (RB) tumor suppressors. Together, these genes regulate complex interconnecting pathways responsible for the regulation of cell growth, cell death, and genomic integrity. Studies in genetically engineered mouse models demonstrate that the canonical functions of these two tumor suppressors fail to fully explain their tumor suppressive capabilities. Individually, p53 and RB have each been implicated in repressing transposons. Here we show that combined loss of p53 and RB, which rapidly transforms cells, also results in cooperative upregulation of transposable elements and coincides with decreased methylation of DNA and H3K9. Our results present a framework by which p53 and RB work together to restrain the expression of LINE1 and SINEs, which may contribute to tumor suppression.

cancer biology↗