Common fragile sites

Arlt, Martin F.; Casper, Anne M.; Glover, Thomas W.

doi:10.1159/000072843

Cited by 114 publications

(97 citation statements)

References 73 publications

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“…Moreover, we show that together with ATR, ATM plays a role in the regulation of fragile site stability via activation of Chk1. Fragile sites were suggested to be involved in different DSB-induced chromosomal aberrations found in many tumor types (Richards, 2001;Arlt et al, 2003), including deletions, translocations and oncogene amplification. Here we show that treatment with 0.4 mM aphidicolin, which induce fragile site expression, leads to DNA fragmentation, providing a direct evidence for DSBs formation under these conditions (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

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Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

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Section: Discussionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

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“…As the CFS regions are so unstable, it has been presumed that genes residing within these regions are frequently altered by the deletions and rearrangements that occur in genetically unstable cancer cells. Therefore, it has been proposed that CFSs, and the genes located within them, play a mechanistic role in the initiation or progression of human cancers (Arlt et al, 2003;Buttel et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

RORA, a large common fragile site gene, is involved in cellular stress response

et al. 2006

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Common fragile sites (CFSs) are large genomic regions present in all individuals that are highly unstable and prone to breakage and rearrangement, especially in cancer cells with genomic instability. Eight of the 90 known CFSs have been precisely defined and five of these span genes that extend from 700 kb to over 1.5 Mb of genomic sequence. Although these genes reside within some of the most unstable chromosomal regions in the human genome, they are highly conserved evolutionarily. These genes are targets for large chromosomal deletions and rearrangements in cancer and are frequently inactivated in multiple tumor types. There is also an association between these genes and cellular responses to stress. Based upon the association between large genes and CFSs, we began to systematically test other large genes derived from chromosomal regions that were known to contain a CFS. In this study, we demonstrate that the 730 kb retinoic acid receptor-related orphan receptor alpha (RORA) gene is derived from the middle of the FRA15A (15q22.2) CFS. Although this gene is expressed in normal breast, prostate and ovarian epithelium, it is frequently inactivated in cancers that arise from these organs. RORA was previously shown to be involved in the cellular response to hypoxia and here we demonstrate changes in the amount of RORA message produced in cells exposed to a variety of different cellular stresses. Our results demonstrate that RORA is another very large CFS gene that is inactivated in multiple tumors. In addition, RORA appears to play a critical role in responses to cellular stress, lending further support to the idea that the large CFS genes function as part of a highly conserved stress response network that is uniquely susceptible to genomic instability in cancer cells.

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“…Aphidicolin (AP), an inhibitor of DNA polymerases a, d and e, is the archetype of CFS-inducing drugs (Glover et al, 1984). Presently, the only sequence properties common to these sites are a high AT content and the presence of clusters of peaks of enhanced flexibility (Mishmar et al, 1998;Arlt et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

et al. 2004

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Fragile sites are classified as common or rare depending on their occurrence in the populations. While rare sites are mainly associated with inherited diseases, common sites have been involved in somatic rearrangements found in the chromosomes of cancer cells. Here we study a mouse locus containing the ionotropic glutamate receptor delta 2 (grid2) gene in which spontaneous chromosome rearrangements occur frequently, giving rise to mutant animals in inbred populations. We identify and clone common fragile sites overlapping the mouse grid2 gene and its human ortholog GRID2, lying respectively at bands 6C1 and 4q22 in a 7-Mb-long region of synteny. These results show a third example of orthologous common sites conserved at the molecular level, and reveal an unexpected link between an inherited disease and an aphidicolin-sensitive region. Recurrent deletions of subregions of band 4q22 have been previously described in human hepatocellular carcinomas. This 15-Mb-long region appears precisely centered on the site described here, which strongly suggests that it also plays a specific role in hepatic carcinogenesis.

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Common fragile sites

Cited by 114 publications

References 73 publications

Interplay between ATM and ATR in the regulation of common fragile site stability

Interplay between ATM and ATR in the regulation of common fragile site stability

RORA, a large common fragile site gene, is involved in cellular stress response

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

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