Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1.
Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly, with small brain sizes reflecting reduced neuron production during fetal life. Although primary microcephaly can be caused by mutations in microcephalin (MCPH1), cells from patients with Seckel syndrome and MOPD II harbor mutations in ataxia telangiectasia and Rad3 related (ATR) or pericentrin (PCNT), leading to disturbed ATR signaling. In this study, we show that a lack of MCPH1 or PCNT results in a loss of Chk1 from centrosomes with subsequently deregulated activation of centrosomal cyclin B-Cdk1.
Tibelius
Alexandra
A
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.
Marhold
Joachim
J
Zentgraf
Hanswalter
H
Heilig
Christoph E
CE
Neitzel
Heidemarie
H
Ducommun
Bernard
B
Rauch
Anita
A
Ho
Anthony D
AD
Bartek
Jiri
J
Krämer
Alwin
A
D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004789:Enzyme Activation; D006801:Humans; D008831:Microcephaly / Q000235:genetics / Q000503:physiopathology; D008938:Mitosis / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
D000941:Antigens; D018797:Cell Cycle Proteins; D019926:Cyclin B; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; C086178:pericentrin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases