The DNA-damage effector checkpoint kinase 1 is essential for chromosome segregation and cytokinesis.
Defective genome maintenance mechanisms, involving DNA repair and cell-cycle checkpoint pathways, initiate genetic instability in many sporadic and hereditary cancers. The DNA damage effector Checkpoint kinase 1 (Chk1) is a critical component of DNA replication, intra-S phase, and G(2)/M phase checkpoints and a recently reported mitotic spindle-assembly checkpoint. Here, we report for the first time that haploinsufficiency of Chk1 in mice resulted in multiple mitotic defects and enhanced binucleation. We observed that Aurora B, a critical cytokinetic regulator and a recently identified Chk1 substrate, was mislocalized in mitotic Chk1(+/-) mammary epithelia. Chk1 also exhibited distinct mitotic localization patterns and was active during unperturbed mitosis and cytokinesis in mammalian cells. Active Chk1 expression was not dependent on treatment with spindle poisons such as colcemid during mitosis and cytokinesis. Furthermore, two different complementary approaches demonstrated that abrogation of Chk1 in mitotic mammalian cells resulted in cytokinetic regression and binucleation, increased chromosome lagging and/or nondisjunction, and abnormal localization of Aurora B at late mitotic structures. Thus, Chk1 is a multifunctional kinase that serves as a nexus between the DNA damage response and the mitotic exit pathways during cell-cycle progression to prevent genomic instability and cancer.
Peddibhotla
Sirisha
S
Interdepartmental Program in Cell and Molecular Biology and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lam
Michael H
MH
Gonzalez-Rimbau
Maria
M
Rosen
Jeffrey M
JM
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D000071877:Checkpoint Kinase 1; D020090:Chromosome Segregation; D048749:Cytokinesis; D004249:DNA Damage; D004847:Epithelial Cells; D006239:Haplotypes; D051379:Mice; D008938:Mitosis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D011494:Protein Kinases; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases