Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability.

International Journal of Molecular Sciences
Guadalupe E Jiménez-GutiérrezBulmaro Cisneros

Abstract

Nuclear β-dystroglycan (β-DG) is involved in the maintenance of nuclear architecture and function. Nonetheless, its relevance in defined nuclear processes remains to be determined. In this study we generated a C2C12 cell-based DG-null model using CRISPR-Cas9 technology to provide insights into the role of β-DG on nuclear processes. Since DG-null cells exhibited decreased levels of lamin B1, we aimed to elucidate the contribution of DG to senescence, owing to the central role of lamin B1 in this pathway. Remarkably, the lack of DG enables C2C12 cells to acquire senescent features, including cell-cycle arrest, increased senescence-associated-β-galactosidase activity, heterochromatin loss, aberrant nuclear morphology and nucleolar disruption. We demonstrated that genomic instability is one driving cause of the senescent phenotype in DG-null cells via the activation of a DNA-damage response associated with mitotic failure, as shown by the presence of multipolar mitotic spindles, which in turn induced the formation of micronuclei and γH2AX foci (DNA-damage marker), telomere shortening and p53/p21 upregulation. Altogether, these events might ultimately lead to premature senescence, impeding the replication of the damaged genome. In s...Continue Reading

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Citations

Aug 23, 2020·International Journal of Molecular Sciences·Wendy Lilián Gómez-MonsivaisBulmaro Cisneros
Mar 7, 2021·International Journal of Molecular Sciences·Calogero Caruso, Annibale Alessandro Puca
May 9, 2021·Cardiovascular Research·Maggie S ChenJessica C Garbern

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Methods Mentioned

BETA
flow cytometry
FACS
Confocal Microscopy

Key Resources (RRID) Mentioned

Addgene_48138

Software Mentioned

Image Lab
ModFit LT
ImageJ

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