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

Guadalupe Elizabeth Jimenez-Gutierrez, Ricardo Mondragon-Gonzalez, Luz Adriana Soto-Ponce, Wendy Lilián Gómez-Monsiváis , Ian García-Aguirre , Ruth Abigail Pacheco-Rivera, Rocío Suárez-Sánchez , Andrea Brancaccio, Jonathan Javier Magaña , Rita C.R. Perlingeiro, Bulmaro Cisneros

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 summary, we present evidence supporting a role for DG in protecting against senescence, through the maintenance of proper lamin B1 expression/localization and proper mitotic spindle organization.
Original languageEnglish
Article number4961
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume21
Issue number14
Early online date14 Jul 2020
DOIs
Publication statusE-pub ahead of print - 14 Jul 2020

Keywords

  • β-Dystroglycan
  • cellular senescence
  • lamin B1
  • DNA-damage response
  • defective mitosis

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