Common fragile sites and genomic instability

 

Yuri Pekarsky, Alessandra Drusco, Eugenio Gaudio, Carlo M Croce, Nicola Zanesi

Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA

Corresponding author: Nicola Zanesi, PhD. 1094 Biomedical Research Tower, 460 W 12th Ave., Columbus, OH 43210, USA
Ph: +1-614-292-3318; Fax: +1-614-292-4097
E-mail: Nicola.Zanesi@osumc.edu

 

June 2013

 

Keywords: CFSs, common fragile sites, aphidicolin, genomic instability, FRA3B, FRA16D, CFS tumor suppressor genes

General features

Specific alterations in the genome that modify the expression of genetic elements involved in the regulation of cell growth and maintenance of genomic integrity are responsible for driving tumorigenesis. These changes are not random, even though each tumor has a particular set of genome alterations. Typically, overexpression of oncogenes and inactivation of tumor suppressor genes occur often and are being extensively studied. Moreover, in malignant cells there is a group of genomic loci that is frequently unstable and contributes actively to tumorigenesis, the common fragile sites (CFSs) (Casper et al., 2012). These regions are non-random sites on chromosomes that under conditions of DNA replication stress, such as mild inhibition of DNA polymerase activity, form gaps and breaks (Glover et al., 1984). As signified by the "common" in their name, CFSs occur at specific chromosome bands of all humans and are a normal component of the chromosomal structure (Durkin et al., 2008). These loci are conserved in other mammals, including, but not limited to, primates and rodents (Fungtammasan et al., 2012). Endogenous and exogenous factors, such as hypoxia, chemotherapeutics and other pharmaceuticals, exposure to radiations, pesticides, cigarette smoke, caffeine and alcohol, may trigger activation of replication fork stress and DNA breaks at CFSs in vivo (Dillon et al., 2010). On the other hand, in vitro, a subset of CFSs (aCFSs) may be induced by aphidicolin, an inhibitor of DNA synthesis that, by affecting DNA polymerases alpha, delta and epsilon, has been shown to activate most fragile sites (Mrasek et al., 2010), inducing gaps that are microscopically visible in metaphase chromosomes.

At the molecular level, the phenomenon of common fragility on chromosomes is still not completely understood (Brueckner et al., 2012). The ATR DNA damage checkpoint pathway has been suggested to have an important role in maintaining the stability of CFSs since a deficiency of proteins associated with this pathway, like ATR, BRCA1, and CHK1, results in increased breakages of CFSs (Casper et al., 2002; Durkin et al., 2008). Moreover, CFSs fragility has been associated with late DNA replication (Debatisse et al., 2006) and histone hypoacetylation (Jiang et al., 2009). It has also been hypothesized that, following DNA replication stress CFSs instability derives from prolonged single-stranded regions of unreplicated DNA accumulating at stalled replication forks that escaped the ATR replication checkpoint (Brueckner et al., 2012). In fact, some aCFSs with delayed late replication due to aphidicolin treatment can enter G2 with only 50% of some aCFSs regions completely replicated (Pelliccia et al., 2008). DNA breakage within aCFSs is thought to derive from failing to complete replication prior to the end of telophase and chromosome segregation (Chan et al., 2009). It has been recently shown that the activity of topoisomerase I is necessary for CFSs fragility due to the requirement for polymerase - helicase uncoupling (Arlt and Glover, 2010). It has been suggested that impaired replication of such regions may be due to the formation of stable secondary structures in their DNA sequences (Burrow et al., 2010; Zlotorynski et al., 2003).

Many of the CFS genomic loci have not yet been molecularly defined. Thus far, the relatively well characterized CFSs are the following: FRA1E, FRA2C, FRA2G, FRA3B, FRA7G, FRA9G, FRA13A, FRA16D, and FRAXB (Brueckner et al., 2012), summarized in Table 1, that are all AT-dinucleotide-rich sites spanning between 300 kb and 1 Mb (Schwartz et al., 2006). Unlike rare fragile sites, in which fragility is attributable to either CGG repeat expansions or AT-rich minisatellites (Sutherland, 2003), in CFSs no such long repeat motifs have been found. However, the nine CFSs defined at molecular level seem to be characterized by segments of discontinuous AT-rich sequences potentially forming secondary structures able to affect replication fork progression and thus leading to chromosomal breakage (Dillon et al., 2010; Zlotorynski et al., 2003). Accordingly, it has been reported that specific DNA sequences, such as [A/T]n and [AT/TA]n repeats, and/or the formation of non-B DNA secondary structures within aCFSs can inhibit replicative DNA polymerases (Shah et al., 2010) and the progression of replication forks (Zhang and Freudenreich, 2007). Recently, scarcity of replication origins, inefficient origin initiation, and failure to activate latent origins have all been proposed to play a role in delayed replication at specific aCFSs (Letessier et al., 2011; Ozeri-Galai et al., 2011).

The Debatisse Laboratory reported the most important new findings in the recent years, showing that CFSs differ in different tissue types and are caused by the paucity of replication origins within the regions - i.e. both FRA3B and FRA16D have replication origins flanking the fragile locus and must replicate the DNA from flanking sites to meet in the middle late S or in G2, in lymphocytes, but the placement of replication origins is different in fibroblasts and these loci are much less fragile in fibroblasts, while different loci are more fragile in fibroblasts. Obviously, this may apply to other tissue types too and shows that the position of fragile regions in specific tissues is due to an epigenetic mechanism that determines the placement of replication origins. This suggests that all the hypothesizing about the effect that specific sequences have in fragile regions may become questionable (Debatisse et al., 2012; Huebner, 2011; Letessier et al., 2011).

Table 1. Association of the best characterized common fragile sites with their chromosome regions and genes affected by their activity. Modified from Saxena, 2012.

While rare fragile sites are generally associated with a single DNA element, several sequence motifs spread along an aCFS locus may determine its fragility (Durkin et al., 2008; Ragland et al., 2008) thus making the characterization of aCFSs a computational challenge (Fungtammasan et al., 2012). However, previous analyses of single aCFSs showed that these loci are enriched in Alu repeats (Tsantoulis et al., 2008), gene-coding regions (Helmrich et al., 2006), histone hypoacetylation (Jiang et al., 2009), high DNA flexibility sequences, and highly AT-rich sequences (Mishmar et al., 1998). Nevertheless, these sequence characteristics seemed not to be associated with the propensity for DNA gaps, breaks, deletions and other genomic rearrangements at CFSs; for example, LINE1 elements are common in the fragile site FRA3B but quite rare in FRA16D, while Alu repeats are dominant in the latter (Ried et al., 2000).

The organization of human chromosomes was traditionally investigated by a variety of banding methods (Comings, 1978). Yunis and Soreng observed that several types of fragile sites are more frequent in R bands that have a relatively high gene and CpG island density and correspond to early replicating genomic regions (Yunis and Soreng, 1984).

Among different CFSs the level of fragility is variable and the most fragile and bestcharacterized CFS in the entire human genome is FRA3B at chromosome band 3p14.2 (Mrasek et al., 2010). The second and third most active CFSs are FRA16D and FRAXB respectively at 16q23.2 and Xp22.3. Generally, in somatic cells CFSs are stable but in many cancers they display frequent chromosomal aberrations. Lung, kidney, breast, and digestive tract malignancies are mainly where heterozygous and homozygous deletions are identified as the most common genomic rearrangements in CFSs (Arlt et al., 2006). All CFSs investigated at molecular level up to now contain protein-coding genes, most of which extend over hundreds of kilobases of DNA (Smith et al., 2007). The FHIT and WWOX genes encompassing FRA3B and FRA16D, respectively, are both > 1 Mb in length and have been shown to exhibit tumor suppressor activity in vivo and in vitro (Drusco et al., 2011; Lewandowska et al., 2009; Saldivar et al., 2010). There are many reports of deletions within CFSs harboring these genes (McAvoy et al., 2007). Actually, the fact that very large genes present in mammalian genomes are preferentially affected by deletions in tumor cells suggests that these genes are all CFSs in the cell type in which they are expressed (Debatisse et al., 2012). Mitotic sister chromatid exchanges are often described at CFSs (Durkin et al., 2008), which suggests that CFS breaks may possibly drive loss of heterozygosity (LOH) in cancer cells when the repair occurs by homologous recombination.

During neoplastic progression, damage at CFS regions seems to be among the earliest occurrences, mainly due to DNA replication stress (Halazonetis et al., 2008) as suggested by the presence of these genomic alterations in pre-neoplastic lesions (Lai et al., 2010). Oncogene amplification and preferred integration sites for some oncogenic viruses are also triggered by CFS activity (Brueckner et al., 2012).

Germline genomic alterations in CFSs seem also to lead to other human illnesses of nonmalignant origin. In support of this possibility is the recent sequencing of breakpoint junctions in the CFS genes PARK2 at FRA6E and DMD at FRAXC in many patients affected, respectively, by juvenile Parkinsonism and muscular dystrophies (Mitsui et al., 2010). Somatic breakpoints in cancer cell lines and germline breakpoints within PARK2 and DMD shared some features that suggested involvement of common mechanisms in the generation of CFS rearrangements.

Recent developments

DNA replication and gene transcription are basic biological processes essential for cell division and growth. Large protein complexes moving at high speed along the chromosomes, and for long distances, make such processes possible. The RNA polymerase II (Pol II) enzyme, in mammalian cells, transcribes 18-72 nucleotides of DNA per second into RNA (Darzacq et al., 2007). One of the longest human loci, the 2.2 Mb dystrophin gene, is transcribed over a period of 16 hours (Tennyson et al., 1995) and similar figures are reported for other long genes. As for typical fast-cycling mammalian cells the cell cycle time is approximately 10 hours, it is expected that these long-term transcription cycles interfere with replication in cell cycle S phase. Unlike in bacteria, transcription and replication in higher eukaryotes are coordinated events that take place within domains spatially and temporally separated (Wei et al., 1998). Usually transcription occurs in G1 phase and sometimes in S phase. When this happens, transcription is thought to be spatially separated from replication sites (Vieira et al., 2004). Gene expression induction in mammalian cells caused recombination processes within the transcription unit, thus suggesting that collisions between replication and transcription complexes provoke instability at the genomic level (Gottipati et al., 2008). Recently, Helmrich et al. demonstrated that the time required to transcribe human genes larger than 800 kb spans more than one complete cell cycle, while their transcription speed is equivalent to that of smaller genes. CFS instability depends on the expression of the underlying long genes and may be suppressed by RNase H1 enzyme when intervenes on R-loops, which are RNA:DNA hybrids between nascent transcripts and the DNA template strand, while the nontemplate strand remains as single-stranded DNA (Helmrich et al., 2011).

The wealth of genome-wide profiling studies now available offers unique opportunities to study causes of genome instability in depth. Current evidence suggests that aCFSs are caused by a series of genomic factors (Dillon et al., 2010). Consequently, building a statistical model that takes into consideration multiple factors simultaneously is thought to be more biologically reliable on the contribution to fragility by the diverse genomic features. Moreover, studies usually do not incorporate in their models the different breakage frequencies of aCFSs.

To better understand the relationship between aCFSs and their genomic contexts, Fungtammasan et al. built statistical models to explain the fragility of well-characterized aCFSs by considering their genomic neighborhoods and comparing them with non-fragile regions (NFRs) (Fungtammasan et al., 2012). The authors focused on aphidicolin-induced CFSs because they are well-characterized genomewide (Mrasek et al., 2010), are the most numerous CFSs, and fragile sites induced by other agents might have different breakage mechanisms and characteristics. Multiple logistic regression was used to predict the probability of a given region to be either an aCFS or an NFR and multiple linear regression for the prediction of expected breakage frequency. Eventually these models were validated using mouse fragile sites (Fungtammasan et al., 2012). Results showed that local genomic features are effective predictors both of regions harboring aCFSs, explaining circa 77% of the deviance in logistic regression models, and of aCFS breakage frequencies, explaining approximately 45% of the variance in standard regression models. In models with the highest explanatory power, aCFSs are mainly located in G-negative chromosomal bands and far from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In addition, aCFSs have high fragility when co-located with evolutionarily conserved chromosomal breakpoints (Fungtammasan et al., 2012).

In order to investigate the mechanisms of CFS-induced breaks, Casper et al. asked whether the flexibility peaks that have been identified within human CFS FRA3B are hotspots of instability (Casper et al., 2012). These authors, to analyze the consequences of CFS breaks, also investigated whether repair of fragile site breaks drives LOH events due to mitotic homologous recombination. To gather detailed data on exact break locations within CFSs, a yeast artificial chromosome (YAC) containing the human locus FRA3B was used. Data suggested that break sites are not randomly distributed, but rather clustered at the centromere-distal end of the FRA3B sequence insert. They also took advantage of a naturally occurring yeast fragile site known as FS2 (fragile site 2) to study mitotic homologous recombination. Similar to human CFSs, recurrent breaks at FS2 occur where replication is impaired because of stressful conditions (Lemoine et al., 2005). Results demonstrated that LOH is, in fact, a consequence of mitotic recombination between homologous chromatids with reciprocal crossovers at FS2 induced by inhibition of yeast DNA polymerase (Casper et al., 2012). Since not many CFSs have been molecularly characterized, despite the growing interest in understanding the precise nature of CFS instability, Brueckner et al. took into consideration the FRA2H CFS and after having fine-mapped the location with six-color fluorescence in situ hybridization, demonstrated that it is one of the most active CFSs in the human genome (Brueckner et al., 2012). FRA2H encompasses approximately 530 kb of a gene-poor region containing a novel large inter-genic non coding RNA gene (AC097500.2). Using custom-designed array comparative genomic hybridization, gross and submicroscopic chromosomal rearrangements were detected, involving FRA2H in a panel of 54 neuroblastoma, colon, and breast cancer cell lines. Genomic alterations often affected different classes of long terminal repeats (LTRs) and long interspersed nuclear elements (LINEs). Sequence analysis of breakpoint junctions revealed that DNA damage repair at FRA2H mostly appeared to occur via non-homologous end-joining events mediated by short micro-homologies (Brueckner et al., 2012).

Deletions at FRA3B CFS occur in pre-neoplasias and may be the most frequent and earliest alterations. FRA3B overlaps the FHIT gene, and its fragility frequently results in deletions of FHIT exons and loss of FHIT expression in precancerous and cancer cells (Sozzi et al., 1998). Examination of cells that have lost FHIT revealed that the protein has some functional roles in response to DNA damage (Saldivar et al., 2010). In particular, kidney epithelial cells established from Fhit-/- mice exhibited >2-fold increased chromosome breaks at fragile sites vs. corresponding Fhit+/+ cells (Turner et al., 2002), and the frequency of mutations following replicative and oxidative stress in Fhit-deficient cells was 2 to 5-fold greater than in Fhit-expressing cells (Ishii et al., 2008; Ottey et al., 2004). Despite these findings and strong evidence that Fhit acts as a tumor suppressor (Joannes et al., 2010; Pekarsky et al., 1998; Siprashvili et al., 1997) it has been proposed that deletions within the FHIT locus are secondary alterations rather than cancer-driving mutations (Bignell et al., 2010). In a new study, Kay Huebner and colleagues (Saldivar et al., 2012) examined further the role of Fhit loss in DNA damage process. Specifically, it has been shown that Fhit loss causes replication stress-induced DNA double-strand breaks in normal, transformed, and cancer-derived cell lines. In Fhit-deficient cells, a defect was observed in replication fork progression that stemmed mainly from fork stalling and collapse. The possible mechanism for the role of Fhit in replication fork progression is by regulation of thymidine kinase 1 expression and thymidine triphosphate pool levels. Interestingly, restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells. Loss of Fhit did not activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosome instability. Such a result was consistent with in vivo studies, where Fhit knockout mouse tissues showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication-sensitive loci. Moreover, cells established from Fhit KO tissues showed rapid immortalization together with DNA deletions and amplifications. Of note, the murine gene Mdm2, an oncogene involved in cell transformation, was also amplified with 4-fold increase in Mdm2 mRNA expression, suggesting that genome instability induced by FHIT depletion facilitates the transformation process. In conclusion, this study proposes that Fhit depletion in precancerous lesions is the first step in the initiation of genomic instability and links alterations at CFSs to the very origin of this important phenomenon (Saldivar et al., 2012).

To conclude this short panoramic on CFSs and genomic instability, we would like to draw the reader's attention to the most recent findings about Polζ polymerase. Polζ, which consists of the catalytic subunit Rev3 and the accessory subunit Rev7, is a trans-lesion DNA synthesis (TLS) polymerase capable of bypassing certain DNA adducts efficiently (Gibbs et al., 1998). Besides its role in TLS, Rev3 is also essential for mouse embryonic development (Bemark et al., 2000), whereas no other TLS polymerases studied to date are required for this fundamental function. Rev3 has been also implicated in homologous recombination repair (Sharma et al., 2012). Because of its extremely large size (>350 kDa), little progress has been made in understanding the essential function of Rev3. Bhat et al. found that the cellular level of Rev3 is elevated in mitotic cells, and the protein is associated with chromatin. Experimental depletion of Rev3 results in elevated CFS expression and chromosomal instability, indicating that Rev3 is required for the late replication of these sites. Rev3 activity is independent of Rev7, as the depletion of cellular Rev7 does not cause CFS expression. Moreover, constitutive depletion of Rev3 in cultured human cells resulted in accumulated genomic instability and eventual arrest of cell division, suggesting that Rev3 is required not only for embryonic development but also for cell viability (Bhat et al., 2013). Interestingly, comparison of yeast and mammalian Rev3 proteins reveals a large exon that is unique to the mammalian gene that will surely be subjected to future investigations for its role in the maintenance of mitotic genomic stability.

Acknowledgements

We thank Dr. Kay Huebner for critical reading of the manuscript and Prasanthi Kumchala for technical assistance. This work was supported by NIH grant U01CA152758 (to CMC).

Bibliography

Mechanisms of chromosome banding and implications for chromosome structure.
Comings DE.
Annu Rev Genet. 1978;12:25-46. (REVIEW)
PMID 85431
 
DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes.
Glover TW, Berger C, Coyle J, Echo B.
Hum Genet. 1984;67(2):136-42.
PMID 6430783
 
Constitutive fragile sites and cancer.
Yunis JJ, Soreng AL.
Science. 1984 Dec 7;226(4679):1199-204.
PMID 6239375
 
The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced.
Tennyson CN, Klamut HJ, Worton RG.
Nat Genet. 1995 Feb;9(2):184-90.
PMID 7719347
 
Replacement of Fhit in cancer cells suppresses tumorigenicity.
Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K.
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13771-6.
PMID 9391102
 
A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta.
Gibbs PE, McGregor WG, Maher VM, Nisson P, Lawrence CW.
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6876-80.
PMID 9618506
 
Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site.
Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE, Margalit H, Platzer M, Weiss A, Tsui LC, Rosenthal A, Kerem B.
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8141-6.
PMID 9653154
 
The murine Fhit locus: isolation, characterization, and expression in normal and tumor cells.
Pekarsky Y, Druck T, Cotticelli MG, Ohta M, Shou J, Mendrola J, Montgomery JC, Buchberg AM, Siracusa LD, Manenti G, Fong LY, Dragani TA, Croce CM, Huebner K.
Cancer Res. 1998 Aug 1;58(15):3401-8.
PMID 9699672
 
Loss of FHIT function in lung cancer and preinvasive bronchial lesions.
Sozzi G, Pastorino U, Moiraghi L, Tagliabue E, Pezzella F, Ghirelli C, Tornielli S, Sard L, Huebner K, Pierotti MA, Croce CM, Pilotti S.
Cancer Res. 1998 Nov 15;58(22):5032-7.
PMID 9823304
 
Segregation of transcription and replication sites into higher order domains.
Wei X, Samarabandu J, Devdhar RS, Siegel AJ, Acharya R, Berezney R.
Science. 1998 Sep 4;281(5382):1502-6.
PMID 9727975
 
Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro.
Bemark M, Khamlichi AA, Davies SL, Neuberger MS.
Curr Biol. 2000 Oct 5;10(19):1213-6.
PMID 11050391
 
Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells.
Ried K, Finnis M, Hobson L, Mangelsdorf M, Dayan S, Nancarrow JK, Woollatt E, Kremmidiotis G, Gardner A, Venter D, Baker E, Richards RI.
Hum Mol Genet. 2000 Jul 1;9(11):1651-63.
PMID 10861292
 
ATR regulates fragile site stability.
Casper AM, Nghiem P, Arlt MF, Glover TW.
Cell. 2002 Dec 13;111(6):779-89.
PMID 12526805
 
The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.
Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, Palazzo J, Huebner K, Popescu NC.
Cancer Res. 2002 Jul 15;62(14):4054-60.
PMID 12124341
 
Rare fragile sites.
Sutherland GR.
Cytogenet Genome Res. 2003;100(1-4):77-84. (REVIEW)
PMID 14526166
 
Molecular basis for expression of common and rare fragile sites.
Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, Hershberg R, Levi A, Scherer SW, Margalit H, Kerem B.
Mol Cell Biol. 2003 Oct;23(20):7143-51.
PMID 14517285
 
Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant.
Ottey M, Han SY, Druck T, Barnoski BL, McCorkell KA, Croce CM, Raventos-Suarez C, Fairchild CR, Wang Y, Huebner K.
Br J Cancer. 2004 Nov 1;91(9):1669-77.
PMID 15494723
 
Recruitment of transcription complexes to the beta-globin gene locus in vivo and in vitro.
Vieira KF, Levings PP, Hill MA, Crusselle VJ, Kang SH, Engel JD, Bungert J.
J Biol Chem. 2004 Nov 26;279(48):50350-7. Epub 2004 Sep 22.
PMID 15385559
 
Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites.
Lemoine FJ, Degtyareva NP, Lobachev K, Petes TD.
Cell. 2005 Mar 11;120(5):587-98.
PMID 15766523
 
Common fragile sites as targets for chromosome rearrangements.
Arlt MF, Durkin SG, Ragland RL, Glover TW.
DNA Repair (Amst). 2006 Sep 8;5(9-10):1126-35. Epub 2006 Jun 27. (REVIEW)
PMID 16807141
 
Common fragile sites nested at the interfaces of early and late-replicating chromosome bands: cis acting components of the G2/M checkpoint?
Debatisse M, El Achkar E, Dutrillaux B.
Cell Cycle. 2006 Mar;5(6):578-81. Epub 2006 Mar 15. (REVIEW)
PMID 16582603
 
Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes.
Helmrich A, Stout-Weider K, Hermann K, Schrock E, Heiden T.
Genome Res. 2006 Oct;16(10):1222-30. Epub 2006 Sep 5.
PMID 16954539
 
The molecular basis of common and rare fragile sites.
Schwartz M, Zlotorynski E, Kerem B.
Cancer Lett. 2006 Jan 28;232(1):13-26. Epub 2005 Oct 19. (REVIEW)
PMID 16236432
 
In vivo dynamics of RNA polymerase II transcription.
Darzacq X, Shav-Tal Y, de Turris V, Brody Y, Shenoy SM, Phair RD, Singer RH.
Nat Struct Mol Biol. 2007 Sep;14(9):796-806. Epub 2007 Aug 5.
PMID 17676063
 
Non-random inactivation of large common fragile site genes in different cancers.
McAvoy S, Ganapathiraju SC, Ducharme-Smith AL, Pritchett JR, Kosari F, Perez DS, Zhu Y, James CD, Smith DI.
Cytogenet Genome Res. 2007;118(2-4):260-9. (REVIEW)
PMID 18000379
 
Large common fragile site genes and cancer.
Smith DI, McAvoy S, Zhu Y, Perez DS.
Semin Cancer Biol. 2007 Feb;17(1):31-41. Epub 2006 Oct 26. (REVIEW)
PMID 17140807
 
An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae.
Zhang H, Freudenreich CH.
Mol Cell. 2007 Aug 3;27(3):367-79.
PMID 17679088
 
Replication stress induces tumor-like microdeletions in FHIT/FRA3B.
Durkin SG, Ragland RL, Arlt MF, Mulle JG, Warren ST, Glover TW.
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):246-51. Epub 2007 Dec 27.
PMID 18162546
 
Transcription-associated recombination is dependent on replication in Mammalian cells.
Gottipati P, Cassel TN, Savolainen L, Helleday T.
Mol Cell Biol. 2008 Jan;28(1):154-64. Epub 2007 Oct 29.
PMID 17967877
 
An oncogene-induced DNA damage model for cancer development.
Halazonetis TD, Gorgoulis VG, Bartek J.
Science. 2008 Mar 7;319(5868):1352-5. doi: 10.1126/science.1140735.
PMID 18323444
 
Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes.
Ishii H, Mimori K, Ishikawa K, Okumura H, Pichiorri F, Druck T, Inoue H, Vecchione A, Saito T, Mori M, Huebner K.
Cancer Res. 2008 May 15;68(10):3662-70. doi: 10.1158/0008-5472.CAN-07-5687.
PMID 18483248
 
Replication timing of two human common fragile sites: FRA1H and FRA2G.
Pelliccia F, Bosco N, Curatolo A, Rocchi A.
Cytogenet Genome Res. 2008;121(3-4):196-200. doi: 10.1159/000138885. Epub 2008 Aug 28.
PMID 18758159
 
Stably transfected common fragile site sequences exhibit instability at ectopic sites.
Ragland RL, Glynn MW, Arlt MF, Glover TW.
Genes Chromosomes Cancer. 2008 Oct;47(10):860-72. doi: 10.1002/gcc.20591.
PMID 18615677
 
Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study.
Tsantoulis PK, Kotsinas A, Sfikakis PP, Evangelou K, Sideridou M, Levy B, Mo L, Kittas C, Wu XR, Papavassiliou AG, Gorgoulis VG.
Oncogene. 2008 May 22;27(23):3256-64. Epub 2007 Dec 17.
PMID 18084328
 
Replication stress induces sister-chromatid bridging at fragile site loci in mitosis.
Chan KL, Palmai-Pallag T, Ying S, Hickson ID.
Nat Cell Biol. 2009 Jun;11(6):753-60. doi: 10.1038/ncb1882. Epub 2009 May 24.
PMID 19465922
 
Common fragile sites are characterized by histone hypoacetylation.
Jiang Y, Lucas I, Young DJ, Davis EM, Karrison T, Rest JS, Le Beau MM.
Hum Mol Genet. 2009 Dec 1;18(23):4501-12. doi: 10.1093/hmg/ddp410. Epub 2009 Aug 28.
PMID 19717471
 
WWOX, the tumour suppressor gene affected in multiple cancers.
Lewandowska U, Zelazowski M, Seta K, Byczewska M, Pluciennik E, Bednarek AK.
J Physiol Pharmacol. 2009 May;60 Suppl 1:47-56. (REVIEW)
PMID 19609013
 
Inhibition of topoisomerase I prevents chromosome breakage at common fragile sites.
Arlt MF, Glover TW.
DNA Repair (Amst). 2010 Jun 4;9(6):678-89. doi: 10.1016/j.dnarep.2010.03.005. Epub 2010 Apr 21.
PMID 20413351
 
Signatures of mutation and selection in the cancer genome.
Bignell GR, Greenman CD, Davies H, Butler AP, Edkins S, Andrews JM, Buck G, Chen L, Beare D, Latimer C, Widaa S, Hinton J, Fahey C, Fu B, Swamy S, Dalgliesh GL, Teh BT, Deloukas P, Yang F, Campbell PJ, Futreal PA, Stratton MR.
Nature. 2010 Feb 18;463(7283):893-8. doi: 10.1038/nature08768.
PMID 20164919
 
Secondary structure formation and DNA instability at fragile site FRA16B.
Burrow AA, Marullo A, Holder LR, Wang YH.
Nucleic Acids Res. 2010 May;38(9):2865-77. doi: 10.1093/nar/gkp1245. Epub 2010 Jan 13.
PMID 20071743
 
DNA instability at chromosomal fragile sites in cancer.
Dillon LW, Burrow AA, Wang YH.
Curr Genomics. 2010 Aug;11(5):326-37. doi: 10.2174/138920210791616699.
PMID 21286310
 
Fhit regulates invasion of lung tumor cells.
Joannes A, Bonnomet A, Bindels S, Polette M, Gilles C, Burlet H, Cutrona J, Zahm JM, Birembaut P, Nawrocki-Raby B.
Oncogene. 2010 Feb 25;29(8):1203-13. doi: 10.1038/onc.2009.418. Epub 2009 Nov 23.
PMID 19935706
 
Deletion at fragile sites is a common and early event in Barrett's esophagus.
Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, Odze R, Sanchez CA, Maley CC, Reid BJ, Gunderson KL, Rabinovitch PS.
Mol Cancer Res. 2010 Aug;8(8):1084-94. doi: 10.1158/1541-7786.MCR-09-0529. Epub 2010 Jul 20.
PMID 20647332
 
Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines.
Mitsui J, Takahashi Y, Goto J, Tomiyama H, Ishikawa S, Yoshino H, Minami N, Smith DI, Lesage S, Aburatani H, Nishino I, Brice A, Hattori N, Tsuji S.
Am J Hum Genet. 2010 Jul 9;87(1):75-89. doi: 10.1016/j.ajhg.2010.06.006.
PMID 20598272
 
Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones.
Mrasek K, Schoder C, Teichmann AC, Behr K, Franze B, Wilhelm K, Blaurock N, Claussen U, Liehr T, Weise A.
Int J Oncol. 2010 Apr;36(4):929-40.
PMID 20198338
 
Pathology and biology associated with the fragile FHIT gene and gene product.
Saldivar JC, Shibata H, Huebner K.
J Cell Biochem. 2010 Apr 1;109(5):858-65. doi: 10.1002/jcb.22481. (REVIEW)
PMID 20082323
 
DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D.
Shah SN, Opresko PL, Meng X, Lee MY, Eckert KA.
Nucleic Acids Res. 2010 Mar;38(4):1149-62. doi: 10.1093/nar/gkp1131. Epub 2009 Dec 6.
PMID 19969545
 
Common fragile site tumor suppressor genes and corresponding mouse models of cancer.
Drusco A, Pekarsky Y, Costinean S, Antenucci A, Conti L, Volinia S, Aqeilan RI, Huebner K, Zanesi N.
J Biomed Biotechnol. 2011;2011:984505. doi: 10.1155/2011/984505. Epub 2010 Dec 29. (REVIEW)
PMID 21318118
 
Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes.
Helmrich A, Ballarino M, Tora L.
Mol Cell. 2011 Dec 23;44(6):966-77. doi: 10.1016/j.molcel.2011.10.013.
PMID 22195969
 
Molecular biology: DNA fragility put into context.
Huebner K.
Nature. 2011 Feb 3;470(7332):46-7. doi: 10.1038/470046a.
PMID 21293366
 
Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site.
Letessier A, Millot GA, Koundrioukoff S, Lachages AM, Vogt N, Hansen RS, Malfoy B, Brison O, Debatisse M.
Nature. 2011 Feb 3;470(7332):120-3. doi: 10.1038/nature09745. Epub 2011 Jan 23.
PMID 21258320
 
Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites.
Ozeri-Galai E, Lebofsky R, Rahat A, Bester AC, Bensimon A, Kerem B.
Mol Cell. 2011 Jul 8;43(1):122-31. doi: 10.1016/j.molcel.2011.05.019.
PMID 21726815
 
Genomic rearrangements at the FRA2H common fragile site frequently involve non-homologous recombination events across LTR and L1(LINE) repeats.
Brueckner LM, Sagulenko E, Hess EM, Zheglo D, Blumrich A, Schwab M, Savelyeva L.
Hum Genet. 2012 Aug;131(8):1345-59. doi: 10.1007/s00439-012-1165-3. Epub 2012 Apr 5.
PMID 22476624
 
Sites of genetic instability in mitosis and cancer.
Casper AM, Rosen DM, Rajula KD.
Ann N Y Acad Sci. 2012 Sep;1267:24-30. doi: 10.1111/j.1749-6632.2012.06592.x.
PMID 22954212
 
Common fragile sites: mechanisms of instability revisited.
Debatisse M, Le Tallec B, Letessier A, Dutrillaux B, Brison O.
Trends Genet. 2012 Jan;28(1):22-32. doi: 10.1016/j.tig.2011.10.003. Epub 2011 Nov 15. (REVIEW)
PMID 22094264
 
A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome?
Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD.
Genome Res. 2012 Jun;22(6):993-1005. doi: 10.1101/gr.134395.111. Epub 2012 Mar 28.
PMID 22456607
 
Initiation of genome instability and preneoplastic processes through loss of Fhit expression.
Saldivar JC, Miuma S, Bene J, Hosseini SA, Shibata H, Sun J, Wheeler LJ, Mathews CK, Huebner K.
PLoS Genet. 2012;8(11):e1003077. doi: 10.1371/journal.pgen.1003077. Epub 2012 Nov 29.
PMID 23209436
 
Are fragile sites "hot-spots": a causative factor in tumor biology.
Saxena AK.
J Exp Ther Oncol. 2012;10(1):19-29. (REVIEW)
PMID 22946341
 
REV1 and polymerase zeta facilitate homologous recombination repair.
Sharma S, Hicks JK, Chute CL, Brennan JR, Ahn JY, Glover TW, Canman CE.
Nucleic Acids Res. 2012 Jan;40(2):682-91. doi: 10.1093/nar/gkr769. Epub 2011 Sep 16.
PMID 21926160
 
Rev3, the catalytic subunit of Pol zeta, is required for maintaining fragile site stability in human cells.
Bhat A, Andersen PL, Qin Z, Xiao W.
Nucleic Acids Res. 2013 Feb 1;41(4):2328-39. doi: 10.1093/nar/gks1442. Epub 2013 Jan 8.
PMID 23303771
 
Written2013-06Yuri Pekarsky, Alessandra Drusco, Eugenio Gaudio, Carlo M Croce, Nicola Zanesi
of Molecular Virology, Immunology,, Medical Genetics, The Ohio State University, Columbus, OH, USA

Citation

This paper should be referenced as such :
Pekarsky, Y ; Drusco, A ; Gaudio, E ; Croce, CM ; Zanesi, N
Common fragile sites, genomic instability
Atlas Genet Cytogenet Oncol Haematol. 2013;17(12):849-855.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Deep/CommFragSitesID20122.htm

Citation

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Common fragile sites and genomic instability

Online version: http://atlasgeneticsoncology.org/deep-insight/20122/common-fragile-sites-and-genomic-instability