Showing papers on "Chromothripsis published in 2003"
TL;DR: Experimental and theoretical evidence for the initiation of chromosomal instability in very early colorectal cancers is explored, and the role that chromosomal stability could have in coloreCTal tumorigenesis is reflected on.
Abstract: A very large fraction of cancers have an abnormal genetic content, called aneuploidy, which is characterized by changes in chromosome structure and number. One explanation for this aneuploidy is chromosomal instability, in which cancer cells gain or lose whole chromosomes or large fractions of chromosomes at a greatly increased rate compared with normal cells. Here, we explore experimental and theoretical evidence for the initiation of chromosomal instability in very early colorectal cancers, and reflect on the role that chromosomal instability could have in colorectal tumorigenesis.
526 citations
TL;DR: It is demonstrated that the frequency and types of repair events depend on the specific genetic context, and this approach can be applied to a number of problems associated with chromosome stability.
Abstract: Chromosomal double-strand breaks (DSBs) can be repaired by either homology-dependent or homology-independent pathways. Nonhomologous repair mechanisms have been relatively less well studied, despite their potential importance in generating chromosomal rearrangements. We have developed a Saccharomyces cerevisiae-based assay to identify and characterize homology-independent chromosomal rearrangements associated with repair of a unique DSB generated within an engineered URA3 gene. Approximately 1% of successfully repaired cells have accompanying chromosomal rearrangements consisting of large insertions, deletions, aberrant gene conversions, or other more complex changes. We have analyzed rearrangements in isogenic wild-type, rad52, yku80, and rad52 yku80 strains, to determine the types of events that occur in the presence or absence of these key repair proteins. Deletions were found in all strain backgrounds, but insertions were dependent upon the presence of Yku80p. A rare RAD52- and YKU80-independent form of deletion was present in all strains. These events were characterized by long one-sided deletions (up to 13 kb) and extensive imperfect overlapping sequences (7-22 bp) at the junctions. Our results demonstrate that the frequency and types of repair events depend on the specific genetic context. This approach can be applied to a number of problems associated with chromosome stability.
91 citations
TL;DR: It is shown that the chromosome integrity function of Orc5p is associated with its ATP-binding motif and is distinct from its function in controlling the efficiency of initiation of DNA replication, which provides potential insights into the counterbalancing selective pressures necessary for the evolution of origin density on chromosomes.
Abstract: The integrity of chromosomes during cell division is ensured by both trans-acting factors and cis-acting chromosomal sites. Failure of either these chromosome integrity determinants (CIDs) can cause chromosomes to be broken and subsequently misrepaired to form gross chromosomal rearrangements (GCRs). We developed a simple and rapid assay for GCRs, exploiting yeast artificial chromosomes (YACs) in Saccharomyces cerevisiae. We used this assay to screen a genome-wide pool of mutants for elevated rates of GCR. The analyses of these mutants define new CIDs (Orc3p, Orc5p, and Ycs4p) and new pathways required for chromosome integrity in DNA replication elongation (Dpb11p), DNA replication initiation (Orc3p and Orc5p), and mitotic condensation (Ycs4p). We show that the chromosome integrity function of Orc5p is associated with its ATP-binding motif and is distinct from its function in controlling the efficiency of initiation of DNA replication. Finally, we used our YAC assay to assess the interplay of trans and cis factors in chromosome integrity. Increasing the number of origins on a YAC suppresses GCR formation in our dpb11 mutant but enhances it in our orc mutants. This result provides potential insights into the counterbalancing selective pressures necessary for the evolution of origin density on chromosomes.
72 citations
Journal Article•
TL;DR: The current knowledge of the licensing system and how this might be defective in cancer cells are reviewed, and the potential of the replication licensing system as a novel anti-cancer target is discussed.
Abstract: The precise duplication of chromosomal DNA during each cell cycle is essential for the maintenance of genetic stability Failure to correctly regulate chromosomal DNA replication could lead to losses or duplication of chromosome segments The precise duplication of chromosomes is normally achieved by correct regulation of the replication licensing system Here we review our current knowledge of the licensing system and how this might be defective in cancer cells We also review how detection of licensing components can be used for the diagnosis and prognosis of cancer Finally we discuss the potential of the replication licensing system as a novel anti-cancer target
19 citations
TL;DR: It is hypothesize that endogenous endonucleases, activated via ‘apoptosis interruptus (AI) in somatic tissue, initiate a portion of chromosomal rearrangements found in cancer.
Abstract: Chromosomal rearrangements are key events in cancer and evolution. These chromosomal rearrangements are dependent upon either legitimate, i.e. homologous, or illegitimate recombination of DNA. Recombi
1 citations