PRJNA732896
DNA replication origins in regenerating mouse livers reveal features of genes and a role of ATR in aging
To help understand how the genome is replicated in mammals, we mapped genome-wide the sites of firing of DNA replication origins in regenerating livers of young and aged mice. In young mice, more than 3,500 origin firing sites were mapped. Monitoring of nascent transcription in vivo under the same conditions revealed that origins were associated with expressed genes, such that about half of all expressed genes had a DNA replication origin dedicated to replication of that gene; this origin could be located either upstream or downstream of the transcribed sequences. In aged mice, origins mapped to the same genomic sites, but firing was very inefficient and entry into S phase was accompanied by induction of a DNA damage response. Remarkably, inhibiting the replication stress checkpoint kinase ATR fully rescued origin firing in old mice, but also led to induction of an inflammatory response at later time points. We propose that genes may have evolved as replication-transcription units carrying their own dedicated replication origins and that suppression of origin firing in regenerating livers of aged mice is an active process mediated by the ATR checkpoin