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 journalArticlepeer-review

1 Scopus citations

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 (US)
Article number4961
Pages (from-to)1-18
Number of pages18
JournalInternational journal of molecular sciences
Volume21
Issue number14
DOIs
StatePublished - Jul 2 2020

Bibliographical note

Funding Information:
Funding: This research was funded by Bilateral Agreement CNR (Italy)/CINVESTAV (Mexico) (Reference CNR2018/4) and SEP-CINVESTAV (Reference 242) grants (BC) and the National Institutes of Health (NHI), grants R01 AR055299 and AR071439 (R.C.R.P.).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • -Dystroglycan
  • Cellular senescence
  • DNA-damage response
  • Defective mitosis
  • Lamin B1

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