TY - JOUR
T1 - Loss of dystroglycan drives cellular senescence via defective mitosis-mediated genomic instability
AU - Jimenez-Gutierrez, Guadalupe Elizabeth
AU - Mondragon-Gonzalez, Ricardo
AU - Soto-Ponce, Luz Adriana
AU - Gómez-Monsiváis, Wendy Lilián
AU - García-Aguirre, Ian
AU - Pacheco-Rivera, Ruth Abigail
AU - Suárez-Sánchez, Rocío
AU - Brancaccio, Andrea
AU - Magaña, Jonathan Javier
AU - Perlingeiro, Rita C.R.
AU - Cisneros, Bulmaro
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7/2
Y1 - 2020/7/2
N2 - 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.
AB - 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.
KW - -Dystroglycan
KW - Cellular senescence
KW - DNA-damage response
KW - Defective mitosis
KW - Lamin B1
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U2 - 10.3390/ijms21144961
DO - 10.3390/ijms21144961
M3 - Article
C2 - 32674290
AN - SCOPUS:85087827327
SN - 1661-6596
VL - 21
SP - 1
EP - 18
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 14
M1 - 4961
ER -