A journey with common fragile sites: From S phase to telophase

Abstract

Some regions of the genome, notably common fragile sites (CFSs), are hypersensitive to replication stress and often involved in the generation of gross chromosome rearrangements in cancer cells. CFSs nest within very large genes and display cell‐type‐dependent instability. Fragile or not, large genes tend to replicate late in S‐phase. A number of data now show that transcription perturbs replication completion across the body of large genes, particularly upon replication stress. However, the molecular mechanisms by which transcription elicits such under‐replication and subsequent instability remain unclear. We present here our view of the mechanisms responsible for CFS under‐replication and those allowing the cells to cope with this problem in G2 and mitosis. We notably focus on the major role played by the FANC proteins in the protection of CFSs from S phase up to late mitosis. We finally discuss a possible rationale for the conservation of large genes across vertebrate evolution.

SMC5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability

“…Remarkably, both our approaches intersected on the FA pathway and particularly FANCD2-I, already reported to play roles in facilitating replication through common fragile sites (CFSs) [21,[55][56][57] and for preventing fragile site expression in the presence or absence of replication stress [45,[58][59][60]. One approach aimed at identifying new interacting partners of SMC5/6 in mammalian cells, while the other addressed the molecular functions of SMC5/6 in DNA repair and genome integrity by examining several mutant combinations in DT40 and upon knockdown in HeLa cells.…”

“…Because FANCC is required for FANCD2 ubiquitylation, which also relies on an intact ATR checkpoint response [42,45], we next ◀ Figure 2. SMC5 contributes to the repair of intra-and inter-strand crosslinks, independently of KU70 and jointly with FANCC.…”

Transcription-mediated organization of the replication initiation program across large genes sets up common fragile sites genome-wide

“…Focussing on 5 large genes, a pioneer work has correlated the tissue-dependent expression of these genes to the instability of associated CFSs 10 . ChIP-Seq of FANCD2, a factor binding preferentially CFSs from S-phase to mitosis upon replication stress 11 , has recently confirmed genome-wide this co-localization of CFSs with large transcribed genes in human 12,13 and chicken 9 cells grown in vitro. Remarkably, the same correlation has been reached upon extensive mapping of copy number variations in large series of tumours 14 .…”

“…The second model is based on molecular combing analyses of the distribution of initiation events along 3 CFSs, showing that the body of hosting genes is origin-poor in normal growth conditions and/or upon stress. Consequently, long-traveling forks emanating from flanking regions replicate those genes 11 . The strong delay to replication completion that specifically occurs when such forks are slowed would elicit CFS instability.…”

“…Replication timing is a second parameter often invoked to explain CFS susceptibility to replication stress. Indeed, late replication would increase the risk of leaving them underreplicated at the time of mitotic entry 11 . But whether and how the replication timing impacts CFS stability remained poorly studied.…”