Transcription-mediated Organization of the Replication Initiation Program Across Large Genes Sets Common Fragile Sites Genome-wide

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Dec 15

PMID 31836700

Citations 60

Authors

Olivier Brison

Sami El-Hilali

Dana Azar

Stephane Koundrioukoff

Melanie Schmidt

Viola Nahse

Yan Jaszczyszyn

Anne-Marie Lachages

Bernard Dutrillaux

Claude Thermes

Michelle Debatisse

Chun-Long Chen

Affiliations

Soon will be listed here.

Abstract

Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide replication timing analyses 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, replicated by long-travelling forks. Forks that travel long in late S phase explains CFS replication features, whereas formation of sequence-dependent fork barriers or head-on transcription-replication conflicts do not. We further show that transcription inhibition during S phase, which suppresses transcription-replication encounters and prevents origin resetting, could not rescue CFS stability. Altogether, our results show that transcription-dependent suppression of initiation events delays replication of large gene bodies, committing them to instability.

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