Disease relevance of Chromosome Breakage

• NO also induces double-stranded chromosomal breaks in replication-arrested Salmonella lacking a functional RecBCD exonuclease [1].
• At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents [2].
• Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13) [3].
• Human melanoma cell lines and tumor tissue from familial and sporadic melanomas have frequent, nonrandom chromosomal breaks and deletions on chromosome 9p21, a region that includes the tumor suppressor gene CDKN2A/p16INK4A [4].
• Peripheral blood lymphocytes from eight Fanconi anemia (FA) patients, 14 FA heterozygotes, and nine normal subjects have been tested for their susceptibility to chromosomal breakage induction by diepoxybutane (DEB) and by two peroxides [5].

Psychiatry related information on Chromosome Breakage

• Progressive vitiligo, mental retardation, facial dysmorphism, and urethral duplication without chromosomal breakage or immunodeficiency [6].

High impact information on Chromosome Breakage

• Cells derived from FA patients show elevated levels of chromosomal breakage and an increased sensitivity to bifunctional alkylating agents such as mitomycin C (MMC) and diepoxybutane (DEB) [7].
• The ATM protein kinase is activated by intermolecular autophosphorylation in response to DNA damage and initiates cellular signaling pathways that facilitate cell survival and reduce chromosomal breakage [8].
• The inability of scid pro-B cells to progress to the pre-B and B cell stages is believed to be caused by a defective recombinase activity that fails to resolve chromosomal breaks resulting from attempted V(D)J recombination [9].
• In this report, we examine human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination [10].
• Molecular characterization of the transduced FACC gene showed an intact unrearranged proviral genome with expression sufficient to normalize cell growth, cell cycle kinetics and chromosomal breakage in the presence of MMC [11].

Chemical compound and disease context of Chromosome Breakage

• We assessed mutagen sensitivity by exposing lymphocytes to bleomycin in vitro and quantitating the bleomycin-induced chromosomal breaks per cell [12].
• These data suggest a contribution of TLS to the prevention of chromosomal breaks by TAM and estrogen, and they therefore indicate that such error-prone DNA synthesis underlies mutagenesis induced by these agents [13].
• Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage [14].
• The clinical response is due in part to the presence of a chromosomal break that occurs in a gene that encodes a nuclear retinoic acid receptor [15].
• Cyclophosphamide-induced oncogenic transformation, chromosomal breakage, and sister chromatid exchange following microsomal activation [16].

Biological context of Chromosome Breakage

• By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells [17].
• We also examined the transcription of the first exon of the c-myc oncogene, which becomes separated from the second and third exon because of the chromosomal break involving the first intron [18].
• This suggests that the chromosomal break, which is paternal in origin and which probably arose at meiosis, has been stabilized in vivo by the direct addition of the telomeric sequence [19].
• We used this technique to analyze mutations in the regulatory region of the Drosophila engrailed gene and found that truncations reduce transcription to levels that depend both upon the tissue and upon the location of the chromosomal break [20].
• In other APL patients who exhibit a 15;17 translocation, we found no genomic changes of the p53, suggesting that the p53 gene, which was recently mapped to the short arm of chromosome 17 in the human, is not structurally related to the typical chromosomal break point found in the long arm of chromosome 17 of APL patients [21].

Anatomical context of Chromosome Breakage

• Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes [22].
• In animals receiving 0.05% phenobarbital for a 12-month period after initiation with DEN, a significant degree of chromosomal breakage and fragment formation occurred both in hepatocytes expressing the ectoenzyme gamma-glutamyltranspeptidase (GGT) and in those that were GGT negative [23].
• Cells cultured from FA patients display elevated spontaneous chromosomal breaks and deletions and are hypersensitive to bifunctional cross-linking agents [24].
• Notably, RAD51 failed to associate with meiotic chromosomes in mutant spermatocytes, despite evidence for the presence of chromosomal breaks [25].
• Female FA patients also displayed a highly significant excess of spontaneous chromosomal breaks versus male patients (P = 0.00026), in the same female:male ratio ( approximately 1.4) as detected for both leukocyte and urine 8-OHdG levels [26].

Gene context of Chromosome Breakage

• Surprisingly, the rad52 xrcc3 double-mutant cells were non-viable and exhibited extensive chromosomal breaks, whereas rad52 and xrcc3 single mutants grew well [27].
• The cells of patients with FA are hypersensitive to DNA cross-linking agents in terms of cell survival and chromosomal breakage [28].
• 2) Dnmt3b-deficient MEF cells showed aneuploidy and polyploidy, chromosomal breaks, and fusions [29].
• Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement [30].
• The presence of this deletion-insertion mutation at cDNA position 565 suggests that this site in the PMM2 gene may be a hotspot for chromosomal breakage [31].

Analytical, diagnostic and therapeutic context of Chromosome Breakage

• The frequency of chromosomal breaks was 2--3 times higher in rodents in comparison with man, after treatment with a dose of 20 mg Cytembena/kg body wt [32].
• Genetic changes and bioassays in bleomycin- and phleomycin-treated cells, and their relationship to chromosomal breaks [33].
• Southern blot analysis showed a chromosomal break in the BCR gene within the 5.8-kilobase (kb) breakpoint cluster region (bcr), between bcr exons 2 and 3 and between bcr exons 3 and 4, respectively [34].

References