Cancer genomes exhibit numerous deletions, some of which inactivate tumor suppressor genes and/or correspond to unstable genomic regions, notably common fragile sites (CFSs). However, 70%-80% of recurrent deletions cataloged in tumors remain unexplained. Recent findings that CFS setting is cell-type dependent prompted us to reevaluate the contribution of CFS to cancer deletions. By combining extensive CFS molecular mapping and a comprehensive analysis of CFS features, we show that the pool of CFSs for all human cell types consists of chromosome regions with genes over 300 kb long, and different subsets of these loci are committed to fragility in different cell types. Interestingly, we find that transcription of large genes does not dictate CFS fragility. We further demonstrate that, like CFSs, cancer deletions are significantly enriched in genes over 300 kb long. We now provide evidence that over 50% of recurrent cancer deletions originate from CFSs associated with large genes.
Replication stress is a primary threat to genome stability and has been implicated in tumorigenesis 1,2 . Common fragile sites (CFSs) are loci hypersensitive to replication stress 3 and are hotspots for chromosomal rearrangements in cancers 4 . CFSs replicate late in S-phase 3 , are cell-type dependent 4-6 and nest within very large genes 4,[7][8][9] . The mechanisms responsible for CFS instability are still discussed, notably the relative impact of transcription-replication conflicts 7,8,10 versus their low density in replication initiation events 5,6 . Here we address the relationships between transcription, replication, gene size and instability by manipulating the transcription of three endogenous large genes, two in chicken and one in human cells.Remarkably, moderate transcription destabilises large genes whereas high transcription levels alleviate their instability. Replication dynamics analyses showed that transcription quantitatively shapes the replication program of large genes, setting both their initiation profile and their replication timing as well as regulating internal fork velocity. Noticeably, high transcription levels advance the replication time of large genes from late to mid S-phase, which most likely gives cells more time to complete replication before mitotic entry.Transcription can therefore contribute to maintaining the integrity of some difficult-toreplicate loci, challenging the dominant view that it is exclusively a threat to genome stability.It is largely agreed that CFSs tend to remain incompletely replicated until mitosis upon replication stress. Incompletely replicated regions are processed by specific endonucleases promoting mitotic DNA synthesis and sister chromatid separation, eventually at the cost of chromosomal rearrangements [11][12][13][14][15] . Two main mechanisms have been suggested to explain this delayed replication completion. One postulates that secondary DNA structures 10 or transcription-dependent replication barriers, notably R-loops 7,8,10 , lead to fork stalling and collapse. The other proposes that replication of the core of the CFSs by long-travelling forks due to their paucity in initiation events is specifically delayed upon fork slowing 5,6 . Here we .
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