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 .

Edited by Vladimir SkulachevKeywords: Frataxin Friedreich ataxia Metacaspase Oxidative stress Yca1 a b s t r a c t Friedreich ataxia is the most common recessive neurodegenerative disease and is caused by reduced expression of mitochondrial frataxin. Frataxin depletion causes impairment in iron-sulfur cluster and heme biosynthesis, disruption of iron homeostasis and hypersensitivity to oxidants. Currently no pharmacological treatment blocks disease progression, although antioxidant therapies proved to benefit patients. We show that sensitivity of yeast frataxin-deficient cells to hydrogen peroxide is partially mediated by the metacaspase. Metacaspase deletion in frataxin-deficient cells results in recovery of antioxidant capacity and heme synthesis. In addition, our results suggest that metacaspase is associated with mitochondrial respiration, intracellular redox control and genomic stability.

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