PMID- 21301226
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20220330
IS  - 1551-4005 (Electronic)
IS  - 1538-4101 (Print)
IS  - 1551-4005 (Linking)
VI  - 10
IP  - 4
DP  - 2011 Feb 15
TI  - Nek1 kinase functions in DNA damage response and checkpoint control through a 
      pathway independent of ATM and ATR.
PG  - 655-63
AB  - Never-in-mitosis A related protein kinase 1 (Nek1) is involved early in a DNA 
      damage sensing/repair pathway. We have previously shown that cells without 
      functional Nek1 fail to activate the more distal kinases Chk1 and Chk2 and fail 
      to arrest properly at G1/S or M-phase checkpoints in response to DNA damage. As a 
      consequence, foci of damaged DNA in Nek1 null cells persist long after the 
      instigating insult, and Nek1 null cells develop unstable chromosomes at a rate 
      much higher than identically cultured wild type cells. Here we show that Nek1 
      functions independently of canonical DNA damage responses requiring the PI3 
      kinase-like proteins ATM and ATR. Chemical inhibitors of ATM/ATR or mutation of 
      the genes that encode them fail to alter the kinase activity of Nek1 or its 
      localization to nuclear foci of DNA damage. Moreover ATM and ATR activities, 
      including the localization of the proteins to DNA damage sites and 
      phosphorylation of early DNA damage response substrates, are intact in Nek1 -/- 
      murine cells and in human cells with Nek1 expression silenced by siRNA. Our 
      results demonstrate that Nek1 is important for proper checkpoint control and 
      characterize for the first time a DNA damage response that does not directly 
      involve one of the known upstream mediator kinases, ATM or ATR.
FAU - Chen, Yumay
AU  - Chen Y
AD  - Department of Medicine, University of California at Irvine, Irvine, CA USA. 
      yumayc@uci.edu
FAU - Chen, Chi-Fen
AU  - Chen CF
FAU - Riley, Daniel J
AU  - Riley DJ
FAU - Chen, Phang-Lang
AU  - Chen PL
LA  - eng
GR  - R01-DK61626/DK/NIDDK NIH HHS/United States
GR  - P50-DK61597/DK/NIDDK NIH HHS/United States
GR  - R01 DK067339/DK/NIDDK NIH HHS/United States
GR  - R01-DK067339/DK/NIDDK NIH HHS/United States
GR  - R01 DK061626/DK/NIDDK NIH HHS/United States
GR  - P50 DK061597/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110215
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (ATMIN protein, human)
RN  - 0 (Androstadienes)
RN  - 0 (Antibodies)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transcription Factors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.11.1 (ATR protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (CHEK1 protein, human)
RN  - EC 2.7.11.1 (CHEK2 protein, human)
RN  - EC 2.7.11.1 (Checkpoint Kinase 1)
RN  - EC 2.7.11.1 (Chek1 protein, mouse)
RN  - EC 2.7.11.1 (Chek2 protein, mouse)
RN  - EC 2.7.11.1 (NEK1 protein, human)
RN  - EC 2.7.11.1 (NIMA-Related Kinase 1)
RN  - EC 2.7.11.1 (Nek1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Antibodies/immunology
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Cycle Proteins/genetics/immunology/*metabolism
MH  - Checkpoint Kinase 1
MH  - Checkpoint Kinase 2
MH  - Chromones/pharmacology
MH  - DNA Breaks, Double-Stranded
MH  - *DNA Damage
MH  - *DNA Repair
MH  - Humans
MH  - Mice
MH  - Morpholines/pharmacology
MH  - NIMA-Related Kinase 1
MH  - Nuclear Proteins/deficiency/genetics/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/deficiency/genetics/immunology/*metabolism
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Transcription Factors
MH  - Wortmannin
PMC - PMC3173995
EDAT- 2011/02/09 06:00
MHDA- 2011/08/31 06:00
PMCR- 2012/02/15
CRDT- 2011/02/09 06:00
PHST- 2011/02/09 06:00 [entrez]
PHST- 2011/02/09 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
PHST- 2012/02/15 00:00 [pmc-release]
AID - 14814 [pii]
AID - 1538-4101-10-4-23 [pii]
AID - 10.4161/cc.10.4.14814 [doi]
PST - ppublish
SO  - Cell Cycle. 2011 Feb 15;10(4):655-63. doi: 10.4161/cc.10.4.14814. Epub 2011 Feb 
      15.