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      Linking abnormal mitosis to the acquisition of DNA damage

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      The Journal of Cell Biology
      The Rockefeller University Press

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          Abstract

          Cellular defects that impair the fidelity of mitosis promote chromosome missegregation and aneuploidy. Increasing evidence reveals that errors in mitosis can also promote the direct and indirect acquisition of DNA damage and chromosome breaks. Consequently, deregulated cell division can devastate the integrity of the normal genome and unleash a variety of oncogenic stimuli that may promote transformation. Recent work has shed light on the mechanisms that link abnormal mitosis with the development of DNA damage, how cells respond to such affronts, and the potential impact on tumorigenesis.

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          Most cited references108

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          Maintaining genome stability at the replication fork.

          Aberrant DNA replication is a major source of the mutations and chromosome rearrangements that are associated with pathological disorders. When replication is compromised, DNA becomes more prone to breakage. Secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymatic activities for their stabilization and subsequent advance. These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions. The mechanisms that operate in eukaryotic cells to promote replication fork integrity and coordinate replication with other aspects of chromosome maintenance are becoming clear.
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            The Stability of Broken Ends of Chromosomes in Zea Mays.

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              Aurora B-mediated abscission checkpoint protects against tetraploidization.

              Genomic abnormalities are often seen in tumor cells, and tetraploidization, which results from failures during cytokinesis, is presumed to be an early step in cancer formation. Here, we report a cell division control mechanism that prevents tetraploidization in human cells with perturbed chromosome segregation. First, we found that Aurora B inactivation promotes completion of cytokinesis by abscission. Chromosome bridges sustained Aurora B activity to posttelophase stages and thereby delayed abscission at stabilized intercellular canals. This was essential to suppress tetraploidization by furrow regression in a pathway further involving the phosphorylation of mitotic kinesin-like protein 1 (Mklp1). We propose that Aurora B is part of a sensor that responds to unsegregated chromatin at the cleavage site. Our study provides evidence that in human cells abscission is coordinated with the completion of chromosome segregation to protect against tetraploidization by furrow regression.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                10 December 2012
                : 199
                : 6
                : 871-881
                Affiliations
                Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115
                Author notes
                Correspondence to Neil J. Ganem: neil_ganem@ 123456dfci.harvard.edu
                Article
                201210040
                10.1083/jcb.201210040
                3518222
                23229895
                039996e5-ba0f-4856-acb8-5a63d1ecdac1
                © 2012 Ganem and Pellman

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 9 October 2012
                : 6 November 2012
                Categories
                Reviews
                Review

                Cell biology
                Cell biology

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