Current models suggest that genomic instability is crucial in the accumulation of the multiple alterations required for tumorigenesis. However, the nature of the initial damage responsible for the origin of genomic instability remains poorly understood. In this investigation we demonstrate that the nucleotide analog 2,6-diaminopurine (DAP) can be used to induce highly focused damage to the larg...

Estimates of the number of chromosomal breakpoints that have arisen (e.g., by translocation and inversion) in the evolutionary past between two species and their common ancestor can be made by comparing map positions of marker loci. Statistical methods for doing so are based on a random-breakage model of chromosomal rearrangement. The model treats all modes of chromosome rearrangement alike, an...

Abstract Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage–fusion–bridge cycles chromothripsis. are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence therefore their contribution instability unchallenged is unknown. To address this issue, we constructed a ge...

Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations, which involve genetic exchange between nonhomologous chromosomes. Here we show that murine Brca2 has an essential function in suppressing GCR formation after chromosome breakage. Cells that harbor truncated Brca2 spontaneously incur GCRs and genomic DNA breaks during division. They exhibit ...

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic qua...

DNA polymerase beta (beta-pol), which is involved in base excision repair, was investigated for its role in protection of cells against various genotoxic agents and cytostatic drugs using beta-pol knockout mouse fibroblasts. We show that cells lacking beta-pol are highly sensitive to induction of apoptosis and chromosomal breakage by methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanid...

Breakage of the fragile site FRA16D disrupts the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor gene in osteosarcoma. However, the frequency of breakage is not sufficient to explain the rate of WWOX loss in pathogenesis. The involvement of non-coding RNA transcripts is proposed due to their accumulation at fragile sites, where they are advocated to influence specific chromosomal re...

DNA has the ability to form a variety of secondary structures that can interfere with normal cellular processes, and many of these structures have been associated with neurological diseases and cancer. Secondary structure-forming sequences are often found at chromosomal fragile sites, which are hotspots for sister chromatid exchange, chromosomal translocations, and deletions. Structures formed ...

Triticeae species have a large and complex genome, which has made it difficult to obtain their sequence data. Some alien chromosomes called the gametocidal (Gc) chromosomes introduced into common wheat can induce chromosomal breakage resulting in the generation of deletions and translocations. The induced deletions have been established as deletion stocks in common wheat. This Gc system is also...