La pauvreté en sites d’initiation de la réplication rend-elle fragile certaines régions du génome ?

Letessier, A; Birnbaum, Daniel; Debatisse, Michèlle; Chaffanet, Max

doi:10.1051/medsci/2011278011

Cited by 4 publications

(6 citation statements)

References 15 publications

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“…Common fragile sites are often caused by a paucity of replication origins and/or collisions of transcription and replication machinery in very long genes [32], [63]. Often, fragile sites remain incompletely replicated as cells progress into mitosis.…”

Section: Discussionmentioning

confidence: 99%

Papillomavirus Genomes Associate with BRD4 to Replicate at Fragile Sites in the Host Genome

2014

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It has long been recognized that oncogenic viruses often integrate close to common fragile sites. The papillomavirus E2 protein, in complex with BRD4, tethers the viral genome to host chromatin to ensure persistent replication. Here, we map these targets to a number of large regions of the human genome and name them Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin or PEB-BLOCs. PEB-BLOCs frequently contain deletions, have increased rates of asynchronous DNA replication, and are associated with many known common fragile sites. Cell specific fragile sites were mapped in human C-33 cervical cells by FANCD2 ChIP-chip, confirming the association with PEB-BLOCs. HPV-infected cells amplify viral DNA in nuclear replication foci and we show that these form adjacent to PEB-BLOCs. We propose that HPV replication, which hijacks host DNA damage responses, occurs adjacent to highly susceptible fragile sites, greatly increasing the chances of integration here, as is found in HPV-associated cancers.

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Section: Discussionmentioning

confidence: 99%

Papillomavirus Genomes Associate with BRD4 to Replicate at Fragile Sites in the Host Genome

2014

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“…When replication forks slow, the likelihood that replication is incomplete at the time of entry into division is increased in the region without initiating events. This contributes to explain the high frequency of breaks observed in CFSs [28]. Furthermore, the analysis of nucleotide-sequence content flanking the breakpoints in CFSs demonstrated junctions with microhomologies to be predominant, favouring the involvement of MMEJ at CFSs [11].…”

Section: The Most Frequent Chromosomal Rearrangements That Occur In Cmentioning

confidence: 86%

Predominance of constitutional chromosomal rearrangements in human chromosomal fragile sites

Sequeira¹,

Mexia²,

Santiago³

et al. 2013

OJGen

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Chromosomal fragile sites (CFSs) are loci or regions susceptible to spontaneous or induced occurrence of gaps, breaks and rearrangements. In this work, we studied the data of 4535 patients stored at DECI-PHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources). We mapped fragile sites to chromosomal bands and divided the 23 chromosomes into fragile and non-fragile sites. The frequency of rearrangements at the chromosomal location of clones found to be deleted or duplicated in the array/CGH analysis, provided by DE-CIPHER, was compared in Chromosomal Fragile Sites vs. non-Fragile Sites of the human genome. The POSSUM Web was used to complement this study. The results indicated 1) a predominance of rearrangements in CFSs, 2) the absence of statistically significant difference between the frequency of rearrangements in common CFSs vs. rare CFSs, 3) a predominance of deletions over duplications in CFSs. These results on constitutional chromosomal rearrangements are evocative of the findings previously reported by others relatively to cancer supporting the current line of evidence and suggesting that a common mechanism can underlie the generation of constitutional and somatic rearrangements. The combination of insights obtained from our results and their interrelationships can indicate strategies by which the mechanisms can be targeted with preventive medical interventions.

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“…De manière surprenante, il existe de nombreuses portions du génome, de plusieurs mégabases, pour lesquelles peu de sites ORC et d'origines sont détectables expé-rimentalement [5,8,10]. Ces régions coïncident fréquemment avec les sites fragiles communs (SFC) du génome 1 [10][11][12] (➜). du complexe ORC.…”

Section: Comment Se Spécifient Les Origines De Réplication ?unclassified

“…En effet, les données accumulées n'ont pas permis une Les SFC sont répliqués très tardivement au cours du cycle cellulaire. Ils sont donc fréquemment sujets à des cassures et des réarrangements lorsque le programme de réplication se prolonge [11,12]. L'absence de ces localisations particulières dans les données obtenues par génomique est probablement associée au fait que les origines de réplication sont distribuées de manière diffuse et variable dans ces portions du génome, ce que les programmes informatiques actuels ne permettent pas d'identifier de manière robuste.…”

Section: Perspectivesunclassified

“…L'absence de ces localisations particulières dans les données obtenues par génomique est probablement associée au fait que les origines de réplication sont distribuées de manière diffuse et variable dans ces portions du génome, ce que les programmes informatiques actuels ne permettent pas d'identifier de manière robuste. L'absence d'origines bien localisées serait ainsi une des causes de la fragilité de ces régions du génome [10][11][12]. Les délétions récurrentes et les régions où s'accumulent les mutations ponctuelles dans les cancers sont, pour la plupart, localisées dans des régions répliquées en fin de phase S [10,[13][14][15].…”

Section: Perspectivesunclassified

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Comment l’approche génomique aide à comprendre le processus d’initiation de la réplication

Miotto

2017

Med Sci (Paris)

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La pauvreté en sites d’initiation de la réplication rend-elle fragile certaines régions du génome ?

Cited by 4 publications

References 15 publications

Papillomavirus Genomes Associate with BRD4 to Replicate at Fragile Sites in the Host Genome

Papillomavirus Genomes Associate with BRD4 to Replicate at Fragile Sites in the Host Genome

Predominance of constitutional chromosomal rearrangements in human chromosomal fragile sites

Comment l’approche génomique aide à comprendre le processus d’initiation de la réplication

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