Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations

Pfeiffer, Petra

doi:10.1093/mutage/15.4.289

Cited by 369 publications

(214 citation statements)

References 191 publications

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“…[35][36][37][38][39] This indicates that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences. 40 Moreover, in all cases, topoisomerase I consensus sequences [A/T-C/G-A/T-T] were found close to the junctions, suggesting that topoisomerase I may participate in the genesis of the EWS/ATF1 chimera (Fig. 2c,d).…”

Section: Discussionmentioning

confidence: 79%

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Panagopoulos

Mertens

Dębiec‐Rychter

et al. 2002

Intl Journal of Cancer

139

119

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Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor particularly associated with tendons and aponeuroses. The cytogenetic hallmark is the translocation t(12;22)(q13; q12) resulting in a chimeric EWS/ATF1 gene in which the 3 -terminal part of EWS at 22q is replaced by the 3 -terminal part of ATF1 at 12q. To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level, and there is no information about the breakpoints at the genomic level. In the present study, we describe the molecular genetic characteristics of CCS from 10 patients. Karyotypes were obtained from 10 cases, 7 of which showed the characteristic t(12;22). As an initial step in the characterization of the EWS/ATF1 and ATF1/EWS chimeras, we constructed an exon/ intron map of the ATF1 gene. The entire ATF1 gene spanned >40 kb and was composed of 7 exons. Intron 3, in which most of the genomic breakpoints occurred, was to a large extent (83%) composed of repetitive elements. RT-PCR amplified EWS/ATF1 cDNA fragments in all patients and ATF1/EWS cDNA fragments in 6 of 10 patients. Four types of EWS/ATF1 chimeric transcript, designated types 1-4, were identified. The most frequent chimeric transcript (type 1) was an inframe fusion of exon 8 of EWS with exon 4 of ATF1. This was the only chimeric transcript in 5 patients but found together with other variants in 3 tumors. The type 2 transcript of EWS/ATF1, an in-frame fusion of exon 7 of EWS with exon 5 of ATF1, was detected in 4 patients, as the only transcript in 1 case and together with other variants in 3 cases. An in-frame fusion of exon 10 of EWS with exon 5 of ATF1 (type 3) was found in 1 patient as the only transcript, and an out-of-frame fusion of EWS exon 7 with ATF1 exon 7 (type 4) was detected in 1 patient together with type 1 and type 2 transcripts. Sequencing of the amplified ATF1/EWS cDNA fragments showed in 5 patients that ATF1 exon 3 was fused with EWS exon 10, resulting in an out-of-frame chimeric transcript. In 1 case, nt 428 of ATF1 (exon 4) was fused with EWS exon 8; at the junction, there was an insertion of 4 nucleotides, also resulting in an out-of-frame transcript. Genomic extra long PCR and sequence analysis mapped the genomic breakpoints to introns 7, 8 and 9 of EWS and intron 3 and exon 4 of ATF1. While a simple end-to-end fusion was observed in 2 cases, additional nucleotides were found at the junctions in 2 other cases. In addition, topoisomerase I consensus sequences were found close to the junctions, suggesting that this enzyme may participate in the genesis of the EWS/ATF1 fusion.

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Section: Discussionmentioning

confidence: 79%

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Panagopoulos

Mertens

Dębiec‐Rychter

et al. 2002

Intl Journal of Cancer

139

119

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“…Sp1 Depletion Renders Cells More Sensitive to DNA Damage GC-rich regions of the genome are unusually sensitive to DNA damage by alkylating agents and represent more open regions of chromatin (48)(49)(50)(51). Because Sp1 binds to GC boxes, we sought to determine the effect of Sp1 depletion on the induction of DSBs by ionizing radiation.…”

Section: The Atm Pathway Mediates the Phosphorylation Of Sp1mentioning

confidence: 99%

Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase

Olofsson

Kelly

Kim

et al. 2007

Molecular Cancer Research

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Sp1, a transcription factor that regulates expression of a wide array of essential genes, contains two SQ/TQ cluster domains, which are characteristic of ATM kinase substrates. ATM substrates are transducers and effectors of the DNA damage response, which involves sensing damage, checkpoint activation, DNA repair, and/or apoptosis. A role for Sp1 in the DNA damage response is supported by our findings: Activation of ATM induces Sp1 phosphorylation with kinetics similar to H2AX; inhibition of ATM activity blocks Sp1 phosphorylation; depletion of Sp1 sensitizes cells to DNA damage and increases the frequency of double strand breaks. We have identified serine 101 as a critical site phosphorylated by ATM; Sp1 with serine 101 mutated to alanine (S101A) is not significantly phosphorylated in response to damage and cannot restore increased sensitivity to DNA damage of cells depleted of Sp1. Together, these data show that Sp1 is a novel ATM substrate that plays a role in the cellular response to DNA damage. (Mol Cancer Res 2007;5(12):1319 -30)

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“…DSBs are a particularly disruptive form of DNA damage that typically must be corrected by the cell prior to its proceeding through the cell cycle [17]. DSBs are known to instigate a variety of genetic alterations, many of which directly increase the risk of tumorigenesis and/or metastasis [18,19]. The sources of these breaks are multi-fold; they can arise from free-radical byproducts of cellular reactions, topoisomerases, ionizing radiation, as well as during the process of meiosis (reviewed in [19,20]).…”

Section: Introductionmentioning

confidence: 99%

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

Hedges

Deininger

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

282

248

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The ubiquity of mobile elements in mammalian genomes poses considerable challenges for the maintenance of genome integrity. The predisposition of mobile elements towards participation in genomic rearrangements is largely a consequence of their interspersed homologous nature. As tracts of nonallelic sequence homology, they have the potential to interact in a disruptive manner during both meiotic recombination and DNA repair processes, resulting in genomic alterations ranging from deletions and duplications to large-scale chromosomal rearrangements. Although the deleterious effects of transposable element (TE) insertion events have been extensively documented, it is arguably through post-insertion genomic instability that they pose the greatest hazard to their host genomes. Despite the periodic generation of important evolutionary innovations, genomic alterations involving TE sequences are far more frequently neutral or deleterious in nature. The potentially negative consequences of this instability are perhaps best illustrated by the 25 human genetic diseases that are attributable to TE-mediated rearrangements. Some of these rearrangements, such as those involving the MLL locus in leukemia and the LDL receptor in familial hypercholesterolemia, represent recurrent mutations that have independently arisen multiple times in human populations. While TE-instability has been a potent force in shaping eukaryotic genomes and a significant source of genetic disease, much concerning the mechanisms governing the frequency and variety of these events remains to be clarified. Here we survey the current state of knowledge regarding the mechanisms underlying mobile element-based genetic instability in mammals. Compared to simpler eukaryotic systems, mammalian cells appear to have several modifications to their DNA-repair ensemble that allow them to better cope with the large amount of interspersed homology that has been generated by TEs. In addition to the disruptive potential of nonallelic sequence homology, we also consider recent evidence suggesting that the endonuclease products of TEs may also play a key role in instigating mammalian genomic instability.

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Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations

Cited by 369 publications

References 191 publications

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

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