title: Homology-mediated end-capping as a primary step of sister chromatid fusion in the breakage-fusion-bridge cycles.
abstract: Breakage-fusion-bridge (BFB) cycle is a series of chromosome breaks and duplications that could lead to the increased copy number of a genomic segment (gene amplification). A critical step of BFB cycles leading to gene amplification is a palindromic fusion of sister chromatids following the rupture of a dicentric chromosome during mitosis. It is currently unknown how sister chromatid fusion is produced from a mitotic break. To delineate the process, we took an integrated genomic, cytogenetic and molecular approach for the recurrent MCL1 amplicon at chromosome 1 in human tumor cells. A newly developed next-generation sequencing-based approach identified a cluster of palindromic fusions within the amplicon at ∼50-kb intervals, indicating a series of breaks and fusions by BFB cycles. The physical location of the amplicon (at the end of a broken chromosome) further indicated BFB cycles as underlying processes. Three palindromic fusions were mediated by the homologies between two nearby inverted Alu repeats, whereas the other two fusions exhibited microhomology-mediated events. Such breakpoint sequences indicate that homology-mediated fold-back capping of broken ends followed by DNA replication is an underlying mechanism of sister chromatid fusion. Our results elucidate nucleotide-level events during BFB cycles and end processing for naturally occurring mitotic breaks.
authors: Department of Molecular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA, Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Frederick, MD 21702, USA, Genomics Facility, University of Chicago, Chicago, IL 60637, USA, Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Department of Molecular Pathology, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors: Michael
authors: M
authors: Marotta
authors: Xiongfong
authors: X
authors: Chen
authors: Takaaki
authors: T
authors: Watanabe
authors: Pieter W
authors: PW
authors: Faber
authors: Scott J
authors: SJ
authors: Diede
authors: Stephen
authors: S
authors: Tapscott
authors: Raymond
authors: R
authors: Tubbs
authors: Anna
authors: A
authors: Kondratova
authors: Robert
authors: R
authors: Stephens
authors: Hisashi
authors: H
authors: Tanaka
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002842:Chromatids / Q000235:genetics*; D019457:Chromosome Breakage; D056905:Chromosome Breakpoints; D005784:Gene Amplification; D023281:Genomics; D006801:Humans; D055029:Inverted Repeat Sequences
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