Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling.
The master checkpoint kinase ATR (ATM and Rad3-related) and its partner ATRIP (ATR-interacting protein) exist as a complex and function together in the DNA damage response. Unexpectedly, we found that the stability of the ATR-ATRIP complex is regulated by an unknown kinase independently of DNA damage. In search for this regulator of ATR-ATRIP, we found that a single member of the NIMA (never in mitosis A)-related kinase family, Nek1, is critical for initiating the ATR response. Upon DNA damage, cells lacking Nek1 failed to efficiently phosphorylate multiple ATR substrates and support ATR autophosphorylation at threnine 1989, one of the earliest events during the ATR response. The ability of Nek1 to promote ATR activation relies on the kinase activity of Nek1 and its interaction with ATR-ATRIP. Importantly, even in undamaged cells, Nek1 is required for maintaining the levels of ATRIP, the association between ATR and ATRIP, and the basal kinase activity of ATR. Thus, as an ATR-associated kinase, Nek1, enhances the stability and activity of ATR-ATRIP before DNA damage, priming ATR-ATRIP for a robust DNA damage response.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Liu_shizhou@hotmail.com
Shizhou
S
Liu
Chu Kwen
CK
Ho
Jian
J
Ouyang
Lee
L
Zou
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D000072380:NIMA-Related Kinase 1; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases