Fos-dependent induction of Chk1 protects osteoblasts from replication stress.
Stable Fos expression in the osteoblast lineage results in the development of osteosarcomas (OS) in mice, yet the underlying mechanisms are poorly understood. Using a genetic system in which Fos expression can be induced in osteoblasts in a doxycycline-dependent manner and through subsequent RNA sequencing and gene set enrichment analysis, we were able to identify novel transcriptional targets of Fos in osteoblasts. These included a distinct activation of cellular response toward replication stress (RS), exemplified by a Fos-dependent induction of the RS-suppressing Chk1 kinase. Importantly, Fos expression protects osteoblasts from RS and DNA damage likely through upregulation of Chk1 and facilitates transformation by Ras/E1A oncogenes. These data reveal a novel function of Fos in safeguarding genome stability during replication, which is particularly relevant in conditions of oncogene-induced S-phase entry.
BBVA Foundation-CNIO Cancer Cell Biology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Jochen
J
Schulze
Genomic Instability Group; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Andres J
AJ
Lopez-Contreras
BBVA Foundation-CNIO Cancer Cell Biology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Özge
Ö
Uluçkan
Bioinformatics Unit; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Osvaldo
O
Graña-Castro
Genomic Instability Group; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Oscar
O
Fernandez-Capetillo
BBVA Foundation-CNIO Cancer Cell Biology Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain.
Erwin F
EF
Wagner
D000818:Animals; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000502:physiology; D004261:DNA Replication / Q000502:physiology*; D055786:Gene Knockout Techniques; D051379:Mice; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016761:Oncogene Proteins v-fos; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse
AP-1; Chk1; DNA damage; Fos; osteoblast; osteosarcoma; replication stress