Contributed by Tess Moskwik, Ph.D.
During mitosis, cells orchestrate the faithful segregation of DNA and cellular material between dividing cells. Progression through mitosis requires the successful completion of the following events: (1) mitotic entry, (2) nuclear envelope break-down, chromosome condensation, and centrosome separation at prophase, (3) kinetochore-microtubule attachment during prometaphase, (4) chromosome congression to the metaphase plate, (5) sister chromatid separation at anaphase, and (6) partitioning of the dividing cells during telophase, cytokinesis and mitotic exit. To ensure that genomic fidelity between dividing cells is preserved, the timing and duration of each step must be highly regulated, and changes in chromosome architecture and microtubule dynamics are required.
During mitosis, transcription is silent, and translation is inhibited (1), thus regulation of mitotic events occurs via post-translational modifications (PTM’s), such as phosphorylation, sumoylation and ubiquitination. For example, mitotic entry requires the kinase activity of the CyclinB1-Cdk1 kinase (2). Centrosome separation is regulated by Aurora A kinase, Polo Kinase 1, and NIMA-related (Nek) kinase 2 (3). The CyclinB1-Cdk1 kinase and Aurora-B kinase regulate chromosome condensation (4). Mitotic spindle assembly, kinetochore-microtubule attachment, and chromosome congression to the metaphase plate are regulated by Polo Kinase 1 and Aurora B kinase (5). Furthermore, Aurora-B controls the spindle assembly checkpoint (MAD2, BUBR1), which ensures that anaphase and sister chromatid separation occur only after all chromosomes are amphitelically attached to opposite spindle poles (6). After anaphase onset, Polo kinase 1 (7) and Aurora B (8) kinase are required for successful anaphase, telophase, and cytokinesis. Interestingly, because localized activation of mitotic kinases drive mitotic progression, the timing, localization, and activity of the kinases themselves are highly regulated by PTM’s such as phosphorylation (Aurora B, Plk1) (9-11) and sumoylation (Aurora-B) (12). Finally, unidirectional progression through mitosis is ensured by ubiquitination by an E3 ubiquitin-ligase, the Anaphase Promoting Complex. Upon binding one of either its adaptors, Cdc20 or Cdh1, the APC ubiquitinates proteins and targets them for degradation. APC/Cdc20 is required for degradation of Cyclin B1 and securin to induce anaphase onset, and APC/Cdh1 is required for degradation of mitotic cyclins and mitotic exit (13). Thus, the regulation of mitosis by post-translational modifications ensure genomic fidelity during cell division.
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