chromosome breakage

..Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers...

..We propose that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage...

..These rearrangements can occur from ectopic gene conversions accompanied by crossing-over, break-induced replication, single-strand annealing or non-homologous end-joining...

..In the absence of Srs2 or Sgs1, DNA damage accumulates and is processed by homologous recombination, triggering repeat rearrangements...

..An understanding of these events will provide insight into the generation of cancer, since deletions and rearrangements at human common fragile sites and associated tumor suppressor genes are an early event in tumorigenesis...

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..The increased gamma ray sensitivity of rad1Delta rad52Delta yku70Delta strains compared to rad52Delta yku70Delta strains suggests that MMEJ also contributes to the repair of DSBs induced by ionizing radiation...

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..Our data suggest that the FRA16D Flex1 sequence causes increased chromosome breakage by forming secondary structures that stall replication fork progression.

..Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion, and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakage-fusion-bridge cycle...

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..Research on genomic disorders on 22q11 will continue to expand our knowledge of the mechanisms of chromosomal rearrangements and the molecular basis of their phenotypic consequences...

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..However, at later steps of repair, alt-NHEJ is a mechanistically distinct pathway of DSB repair, and thus may play a unique role in mutagenesis during cancer development and therapy...

..Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression...

..This represents a major contribution to chromosome breakage. The presence of chromosome breaks in cells released from checkpoint arrest suggests that release occurs ..

..In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions...

..This dynamic process could function to promote gene conversion by capture of the displaced invading strand at two-ended DSBs to prevent BIR...

..The mean frequency of chromosome breakage per 10 000 cells scored in sperm-FISH for FF and F24 was 10.5 +/- 1.3 breaks and 11.2 +/- 1...

..Distinguishing the effect of TP53 codon-72 variations from other modifiers of G2-chromosome radiosensitivity might aid in identifying new markers of cancer risk...

..Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis...

..Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations...

..Deletion of the interaction domain from BLM fails to correct the elevated chromosome breakage of transfected BLM-deficient cells...

..Cultures with an increased frequency of chromosome breakage had a slightly higher mitotic index than controls...

..We conclude that the inability to properly repair strand breaks by homology-directed repair gives rise to defects in chromosome maintenance that promote genetic instability and, it is likely, tumorigenesis...

..Interestingly, in a direct comparison, the spectrum of translocation breakpoint junctions differed from junctions derived from repair at a single chromosomal break, providing mechanistic insight into translocation formation...

..Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process...

..Other potential genes responsible for intellectual deficiency disrupted as a result of patient's chromosomal rearrangement map at 12q14.1 (TAFA2), 12q23.1 (METAP2), and 11p14.1 (BDNF)...

..40 versus 0.39). Oral selenium is a good candidate for chemoprevention in women who carry a mutation in the BRCA1 gene...

..We also estimated the rate of rearrangement between D. repleta and D. buzzatii and conclude that rates within the genus Drosophila vary substantially between lineages, even within a single species group...

..In contrast, we investigate whether this regional fragility is an inherent genomic characteristic and is thus conserved over multiple independent lineages...

..These results demonstrate that chromosome breakage in evolution is nonrandom and that HSBs and EBRs are evolving in distinctly different ways...

..Therefore, an unknown mechanism appears to be involved in the generation of CDKN2A deletions during carcinogenesis...

..HBV patients and 20 chronic HBV carriers were cultured in order to make cytogenetic evaluation by observing chromosome breakage and cytological evaluation by the micronucleus (MN) test...

..More than 80% of these evolutionary breakpoints are located in chromosome bands that express FSs and/or contain ITSs...

..Moreover, a gene associated to hereditary schizophrenia maps within FRA6F. Therefore, FRA6F may represent a landmark for the identification and cloning of genes involved in senescence, leukemia, cancer and schizophrenia...

..Each defect involves a separate protein in these complex pathways...

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..004). The BP2/3 inversion should be an intermediate estate that facilitates the occurrence of 15q11-q13 BP2/3 deletions in the offspring...

..In 11 deletions analyzed, breakpoints were explicable by non-B DNA structure formation. We conclude that alternative DNA conformations trigger genomic rearrangements through recombination-repair activities...

..Here, we show that null mutations in the Drosophila mre11 and rad50 genes cause both telomeric fusion and chromosome breakage. Moreover, we demonstrate that these mutations are in the same epistasis group required for telomere ..

..Reproductive isolation and subsequent speciation are thought to be the potential result of pericentric inversions, as reproductive boundaries form as a result of hybrid sterility...

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..The other patient had a breakpoint more proximal to this region. The present data together with these from the literature provide evidence that a region within 7q21.11 may be prone to breakage and formation of CCRs...

..These findings coincide with the trend observed in hominoid karyotype evolution that humans have a karyotype close to an ancestral one, while African great apes present with more derived chromosome arrangements...

..Our analysis implies that the rate of rearrangements is much higher in murid rodents than in the human lineage and confirms the existence of rearrangement hot-spots in all three lineages...

..Although VACTERL with hydrocephaly has clearly been associated with FA, the indication for chromosome breakage studies is not clear in VACTERL without hydrocephaly...

..We suggest that high-density CGH array analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions...

..To accurately identify small segments of CNA from SNP array data, segmentation methods that are sensitive to CNA while resistant to noise are required...

..Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells...

..The present study demonstrates that DNA damage occurs after both the microinjection of pronuclei and ICSI-mediated transgenesis, albeit through different mechanisms...

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..Contrary to current methods which search for synteny blocks and simply return what remains in the genome as breakpoints, we propose to go further and to investigate the breakpoints themselves in order to refine them...

..Collectively, these results describe a position effect that downregulates TRPS1 expression as the probable cause of hypertrichosis in AS in humans and the Koa phenotype in mice...

..In this work, we have explored the presence of interspersed repeats in regions of chromosomal rearrangements, using an updated high-resolution integrated comparative map among cattle, man and mouse...

..These findings demonstrate a critical role for the CHK1 kinase in regulating chromosome stability, and in particular, common fragile site stability...

..Analytic and simulation methods show that reuse is very sensitive to the proportion of blocks excluded. As is pertinent to the comparison of mammalian genomes, this exclusion risks randomizing the comparison partially or entirely...

..More generally, our analyses suggest an evolutionary cycle between segmental polymorphisms and genome rearrangements...

..Thus, the most parsimonious interpretation is that the gorilla and chimpanzee homologs exhibit similar but nonidentical derived pericentric inversions, whereas HSA 16 represents the ancestral form among hominoids...

..Rather, we propose that high G+C sequences are found preferentially within dog subtelomeres as a direct consequence of chromosomal fission occurring more frequently within regions elevated in G+C...

..As cellular p53 status does not markedly influence the frequency of such events, our results also have implications for how p53 and the DSB response machinery cooperate to suppress generation of lymphomas with oncogenic translocations...

..The derived position of 2L+a, long considered ancestral in this medically important group, has significant implications for the phylogenetic history and the evolution of vectorial capacity in the A. gambiae complex...

..The discovery of cryptic events in seemingly simple chromosome rearrangements may provide the basis for proposing mechanisms of formation...

..Not surprisingly, defects in these networks result in a variety of diseases ranging from severe genetic disorders to cancer predisposition and accelerated ageing...

..Furthermore, we find that individual genetic factors play distinct roles during repair of non-cohesive DSB ends that are generated via co-expression of I-SceI with Trex2...

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..Instead, as yet unidentified DNA conformation or nucleotide characteristics peculiar to the preferentially recombining regions, including those Alu elements present within them, more likely influence their fragility...

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..Our data suggest that lack of expression of these sequences contributes to the PWS phenotype...

..Because interpretation of the results is straightforward and requires no extensive experience, this assay may be the best available diagnostic test for BCL2 rearrangement. Genes Chromosomes Cancer 27:85-94, 2000...

..This suggests that defects in the suppression of rearrangements involving divergent, repeated sequences may underlie the genome instability seen in BLM and WRN patients and in cancer cases associated with defects in these genes...

..e. ICF syndrome or 5-azacytidine treatment...

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..The breakpoints of translocations are strongly associated with dispersed repeats and gene family members in the C. elegans genome...

..Finally, we sequenced breakpoints of all 15 evolutionary rearrangements, providing a view of the forces that drive chromosome evolution in mammals...

..5 Mb of the complete 1p36 band. This could explain its proneness for involvement in chromosomal rearrangements in hematological neoplasias...

..This study highlights the importance of combining high-resolution chromosome and FISH with BACs in order to make genotype-phenotype correlations and to understand the mechanisms involved chromosomal aberrations...

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..We therefore speculate that physical constraints on chromosomal movement are modulated during DSB repair, to facilitate the homology search throughout the genome...

..NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool...

..We review the cytogenetic molecular data concerning the proximal inversion breakpoint of 11q and confirm its heterogeneity...

..Involvement of MORF in four uterine leiomyomata with chromosomal rearrangements involving 10q22 and 17q21 suggests a role for this histone acetyltransferase and altered chromatin regulation in uterine mesenchymal neoplasia...

..ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses...

..Oncogene (2001) 20, 48 - 57...

..Because the majority of these breakpoints have been reported previously in MM, our results support the idea of common mechanisms in this disease...

..Conventional cytogenetics continues to be valuable detecting the presence of non-random chromosomal breakpoints and facilitating the identification of genes implicated in tumorigenesis...

..We also showed that array results might impact the recurrence risks for relatives of affected individuals. Our data indicate that chromosome rearrangements frequently involve more breaks than current cytogenetic models assume...

..To our knowledge, this is the first molecular analysis of the gonosomal complement in spermatozoa of men with a t(X;Y)(qter-->p22::q11-->qter)...

..These results emphasize the fluidity of mammalian DSB repair pathway usage. The intron-based system is highly adaptable to addressing a number of issues regarding molecular mechanisms of genomic rearrangements in mammalian cells...

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..We demonstrate that array comparative genomic hybridisation (CGH) is a useful complementary tool to cytogenetic analysis for detecting and mapping cryptic imbalances associated with chromosome rearrangement...

..However, comparable effects were induced in MCF-7 cells by a much lower dose than in WiDr cells. Insertions were also induced more efficiently in MCF-7 cells than in WiDr cells...

..We detail the most complicated familial complex chromosomal rearrangement reported to date and thus an extreme example of inheritance of chromosomal rearrangements without error in meiotic segregation...

..21-20p11.22 delineated by BAC/PAC clones RP11-96L6 and RP13-401N8. Thus, i(20q-) could be more precisely described as a der(20)del(20)(q11q13)idic(20)(p11)...

..The very high frequency of 13q14 loss suggests that these deletions are of pathogenetic importance, but, the importance of the translocations remains to be determined...

..Nonetheless, further detailed molecular analysis will be necessary in the future to characterize the mechanisms and genetic basis for this phenomenon...

..1. The present case suggests that array-CGH can uncover cryptic genomic aberrations affecting atypical phenotypes even in well-known congenital disorders...

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..Finally, the translocation breakpoints located within BP6 result in very large proximal 15q deletions providing new informative genotype-phenotype correlations...

..we will again use genome wide approaches, which will identify Pfh1 binding sites, as well as sites of chromosome breakage upon Pfh1 depletion...

..We will investigate what makes these other sites targets for AID, and for DNA break formation. Thus our studies will also shed light on the important question of how AID chooses its targets. ..

..breaks, examine early post-fertilization events after ICSI with treated spermatozoa, and test if paternal chromosome breakage can be observed in the absence of ICSI, to exclude the possibility that observed chromosome breakage is an ..

..We will investigate what makes these other sites targets for AID, and for DNA break formation. Thus our studies will also shed light on the important question of how AID chooses its targets. ..

..This grant proposal seeks funding to conduct these clinical trials and further develop retrovirus-mediated complementation analysis in a CAP/CLIA environment for use in clinical management of FA patients. ..

..This grant proposal seeks funding to conduct these clinical trials and further develop retrovirus-mediated complementation analysis in a CAP/CLIA environment for use in clinical management of FA patients. ..

..This grant proposal seeks funding to conduct these clinical trials and further develop retrovirus-mediated complementation analysis in a CAP/CLIA environment for use in clinical management of FA patients. ..

..Identification of new proteins and elucidation of FA pathway mechanisms will help uncover a new realm of cancer biology and directly provide clinical applicability. ..

..we will again use genome wide approaches, which will identify Pfh1 binding sites, as well as sites of chromosome breakage upon Pfh1 depletion...

..Identification of new proteins and elucidation of FA pathway mechanisms promise to shed light on a novel area of cancer biology with the potential to provide direct clinical applicability. ..

..Evidence now suggests the presence of four hotspots for chromosome breakage in this region: two proximal to the PWS/AS region and two distal...

..The map will also include two other types of STS: 1) chromosome breakage junctions, to serve as the well defined ends to the physical map of each macronuclear chromosome fragment ..

..Failure to activate or to coordinate the DNA-damage induced signal transduction pathways can lead to chromosome breakage and loss, and to the propagation of mutations...

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..Past studies by this and other laboratories have revealed two major processes: site specific chromosome breakage and DNA deletion...

..The completion of the proposed work can lead to the identification of biochemical factors that increase or decrease individual susceptibility to genetic damage by carcinogenic chromium. ..

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..To identify DNA of the fragile X site, a somatic cell hybrid system was developed that can monitor chromosome breakage within or near the fragile X site...