Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control.
Nek1, the first mammalian ortholog of the fungal protein kinase never in mitosis A, is involved early in the DNA damage sensing/repair pathway after ionizing radiation. Here we extend this finding by showing that Nek1 localizes to nuclear foci of DNA damage in response to many different types of damage in addition to IR. Untransformed cells established from kat2J/Nek1(-/-) mice fail to arrest properly at G(1)/S and M-phase checkpoints in response to DNA damage. G(1)-S-phase checkpoint control can be rescued by ectopically overexpressing wild-type Nek1. In Nek1(-/-) murine cells and in human cells with Nek1 expression silenced by siRNA, the checkpoint kinases Chk1 and Chk2 fail to be activated properly in response to ionizing or UV radiation. In cells without functional Nek1, DNA is not repaired properly, double-stranded DNA breaks persist long after low dose IR, and excessive numbers of chromosome breaks are observed. These data show that Nek1 is important for efficient DNA damage checkpoint control and for proper DNA damage repair.
Chen
Yumay
Y
Department of Medicine, Division of Nephrology, The University of Texas Health Science Center at San Antonio, Texas 78229-3900, USA. cheny@uthscsa.edu
Chen
Phang-Lang
PL
Chen
Chi-Fen
CF
Jiang
Xianzhi
X
Riley
Daniel J
DJ
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000072380:NIMA-Related Kinase 1; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D011993:Recombinant Fusion Proteins; D004247:DNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; C000606920:Nek1 protein, mouse; D017346:Protein Serine-Threonine Kinases