RT Journal Article
SR Electronic
T1 Transcription-mediated organization of the replication initiation program across large genes sets up common fragile sites genome-wide
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 714717
DO 10.1101/714717
A1 Olivier Brison
A1 Sami EL-Hilali
A1 Dana Azar
A1 Stéphane Koundrioukoff
A1 Mélanie Schmidt
A1 Viola Naehse-Kumpf
A1 Yan Jaszczyszyn
A1 Anne-Marie Lachages
A1 Bernard Dutrillaux
A1 Claude Thermes
A1 Michelle Debatisse
A1 Chun-Long Chen
YR 2019
UL http://biorxiv.org/content/early/2019/07/25/714717.abstract
AB Common Fragile Sites (CFSs) are chromosome regions prone to breakage under replication stress, known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription elicits their instability but the underlying mechanisms remained elusive. Analyses of genome-wide replication timing of human lymphoblasts here show that stress-induced delayed/under-replication is the hallmark of CFSs. Extensive genome-wide analyses of nascent transcripts, replication origin positioning and fork directionality reveal that 80% of CFSs nest in large transcribed domains poor in initiation events, thus replicated by long-traveling forks. In contrast to formation of sequence-dependent fork barriers or head-on transcription-replication conflicts, traveling-long in late S phase explains CFS replication features. We further show that transcription inhibition during the S phase, which excludes the setting of new replication origins, fails to rescue CFS stability. Altogether, results show that transcription-dependent suppression of initiation events delays replication of large gene body, committing them to instability.