In vivo DNA replication dynamics unveil aging-dependent replication stress
Giacomo Rossetti, Noëlle Dommann, Angeliki Karamichali, Vasilis S. Dionellis, A Asensio Aldave, Tural Yarahmadov, Eddie Rodríguez-Carballo, Adrian Keogh, Daniel Candinas, Deborah Stroka, Thanos D. Halazonetis
Abstract
The genome duplication program is affected by multiple factors in vivo, including developmental cues, genotoxic stress, and aging. Here, we monitored DNA replication initiation dynamics in regenerating livers of young and old mice after partial hepatectomy to investigate the impact of aging. In young mice, the origin firing sites were well defined; the majority were located 10-50 kb upstream or downstream of expressed genes, and their position on the genome was conserved in human cells. Old mice displayed the same replication initiation sites, but origin firing was inefficient and accompanied by a replication stress response. Inhibitors of the ATR checkpoint kinase fully restored origin firing efficiency in the old mice but at the expense of an inflammatory response and without significantly enhancing the fraction of hepatocytes entering the cell cycle. These findings unveil aging-dependent replication stress and a crucial role of ATR in mitigating the stress-associated inflammation, a hallmark of aging.