title: INK4a/ARF limits the expansion of cells suffering from replication stress.
abstract: Replication stress (RS) is a source of DNA damage that has been linked to cancer and aging, which is suppressed by the ATR kinase. In mice, reduced ATR levels in a model of the ATR-Seckel syndrome lead to RS and accelerated aging. Similarly, ATR-Seckel embryonic fibroblasts (MEF) accumulate RS and undergo cellular senescence. We previously showed that senescence of ATR-Seckel MEF cannot be rescued by p53-deletion. Here, we show that the genetic ablation of the INK4a/Arf locus fully rescues senescence on ATR mutant MEF, but also that induced by other conditions that generate RS such as low doses of hydroxyurea or ATR inhibitors. In addition, we show that a persistent exposure to RS leads to increased levels of INK4a/Arf products, revealing that INK4a/ARF behaves as a bona fide RS checkpoint. Our data reveal an unknown role for INK4a/ARF in limiting the expansion of cells suffering from persistent replication stress, linking this well-known tumor suppressor to the maintenance of genomic integrity.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Monasor
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Lopez-Contreras
authors.forename: Carolina
authors.initials: C
authors.lastname: Navas
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: ATR; DNA damage; H2AX; INK4a/ARF; replicative stress