INK4a/ARF limits the expansion of cells suffering from replication stress

TY - JOUR

T1 - INK4a/ARF limits the expansion of cells suffering from replication stress

AU - Monasor, Angela

AU - Murga, Matilde

AU - Lopez-Contreras, Andres J

AU - Navas, Carolina

AU - Gomez, Gonzalo

AU - Pisano, David G

AU - Fernandez-Capetillo, Oscar

PY - 2013/6/15

Y1 - 2013/6/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Cyclin-Dependent Kinase Inhibitor p16

KW - DNA Damage

KW - DNA Replication

KW - Immunoblotting

KW - Immunohistochemistry

KW - Mice

U2 - 10.4161/cc.25017

DO - 10.4161/cc.25017

M3 - Journal article

C2 - 23676215

SN - 1538-4101

VL - 12

SP - 1948

EP - 1954

JO - Cell Cycle

JF - Cell Cycle

IS - 12

ER -