Abstract
Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.
Highlights
Chromosomal instability (CIN) is a major form of genome instability representing a hallmark of cancer [1, 2]
Our work demonstrates that mildly increased CDK1 activity is sufficient to trigger whole chromosome missegregation in mitosis and whole chromosome instability (W-CIN) in otherwise chromosomally stable human cells
It is currently not understood in detail how increased microtubule polymerization rates cause chromosome missegregation, but existing data indicate that abnormal microtubule polymerization rates trigger transient spindle mispositioning, thereby facilitating the generation of erroneous merotelic microtubule-kinetochore attachments and inducing lagging chromosomes during anaphase as a pre-stage of chromosome missegregation [10]
Summary
Chromosomal instability (CIN) is a major form of genome instability representing a hallmark of cancer [1, 2]. A majority of cancer cells shows aneuploidy that is strongly associated with tumorigenesis, tumor progression, therapy resistance, and poor prognosis [3]. Despite the strong link between increased mitotic microtubule assembly rates and W-CIN, the cancer-associated genetic alterations leading to abnormal microtubule dynamics are not well understood. Only a few tumor suppressors and oncogenes including BRCA1, CHK2, AURKA, and CEP72 were shown to be involved in triggering W-CIN by increasing mitotic microtubule assembly rates [10,11,12,13,14,15]
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