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Guarding the Genome: Centromeres, the Mitotic Checkpoint and Tumorigenesis
Author(s) -
Cleveland Don
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a148
Subject(s) - centromere , biology , spindle checkpoint , kinetochore , chromosome instability , anaphase , microbiology and biotechnology , aneuploidy , mitosis , genetics , cell cycle , chromosome , cancer , gene
Although the centromere is the basic element of chromosome inheritance, centromere function in mammals is specified not by DNA sequence, but by an undefined epigenetic mark. CENP‐A, a histone variant that replaces H3 only at functional centromeres, is shown to confer a unique conformational rigidity to nucleosomes, providing the basis for such an epigenetic mark. Unattached centromeres are responsible for the mitotic checkpoint, the major cell cycle control mechanism that acts to maintain diploid chromosome content. Prevention of premature onset of anaphase requires activation at unattached centromeres of the BubR1 kinase, which with other components generates a diffusible “wait anaphase” inhibitor. The centromere‐associated kinesin family member CENP‐E is the cyclin‐like activator of BubR1. Spindle microtubule capture by CENP‐E silences BubR1 activity. Thus, CENP‐E is the signal transducing linker responsible for activating and silencing BubR1‐dependent mitotic checkpoint signaling. Reduced levels of CENP‐E weaken the checkpoint, producing near diploid aneuploidy from missegregation of whole chromosomes. Such aneuploidy drives spontaneous lymphomas and lung tumors. Conversely, aneuploidy is an inhibitor of tumors initiated by loss of the p19 tumor suppressor, revealing a previously unsuspected role of chromosomal instability in preventing tumorigenesis.