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

Debatisse, Michèlle; Rosselli, Filippo

doi:10.1002/gcc.22704

Cited by 36 publications

(45 citation statements)

References 94 publications

(265 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra-and inter-strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA-like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non-additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2-I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA-related human disorders.

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Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Smc5/6 Function Is Required For Normal Proliferation In Dt40mentioning

confidence: 99%

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

et al. 2019

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“…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 .…”

Section: Introductionmentioning

confidence: 86%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Brison

Koundrioukoff

Schmidt

et al. 2019

Preprint

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Running title (50 characters or less, including spaces)CFSs: a view through Repli-Seq, GRO-seq and OK-Seq ABSTRACT 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, travelinglong 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.

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Sites of chromosomal instability in the context of nuclear architecture and function

Pentzold

Kokal

Pentzold

et al. 2020

Cell. Mol. Life Sci.

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Chromosomal fragile sites are described as areas within the tightly packed mitotic chromatin that appear as breaks or gaps mostly tracing back to a loosened structure and not a real nicked break within the DNA molecule. Most facts about fragile sites result from studies in mitotic cells, mainly during metaphase and mainly in lymphocytes. Here, we synthesize facts about the genomic regions that are prone to form gaps and breaks on metaphase chromosomes in the context of interphase. We conclude that nuclear architecture shapes the activity profile of the cell, i.e. replication timing and transcriptional activity, thereby influencing genomic integrity during interphase with the potential to cause fragility in mitosis. We further propose fragile sites as examples of regions specifically positioned in the interphase nucleus with putative anchoring points at the nuclear lamina to enable a tightly regulated replication–transcription profile and diverse signalling functions in the cell. Consequently, fragility starts before the actual display as chromosomal breakage in metaphase to balance the initial contradiction of cellular overgrowth or malfunctioning and maintaining diversity in molecular evolution.

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

Cited by 36 publications

References 94 publications

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

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

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

Sites of chromosomal instability in the context of nuclear architecture and function

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