Human Tousled like kinases are targeted by an ATM‐ and Chk1‐dependent DNA damage checkpoint

All eukaryotes respond to DNA damage by modulation of diverse cellular processes to preserve genomic integrity and ensure survival. Here we identify mammalian Tousled like kinases (Tlks) as a novel target of the DNA damage checkpoint. During S‐phase progression, when Tlks are maximally active, gener...

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Bibliographic Details
Published in:The EMBO journal 2003-04, Vol.22 (7), p.1676-1687
Main Authors: Groth, Anja, Lukas, Jiri, Nigg, Erich A., Silljé, Herman H. W., Wernstedt, Christer, Bartek, Jiri, Hansen, Klaus
Format: Article
Language:English
Subjects:
Ataxia Telangiectasia Mutated Proteins
ATM
Base Sequence
Caffeine
Cell Cycle Proteins
Cell Line
Checkpoint Kinase 1
checkpoints
Chk1
chromatin assembly
Deoxyribonucleic acid
DNA
DNA Damage
DNA Primers
DNA-Binding Proteins
EMBO06
EMBO13
Humans
Mutagenesis, Site-Directed
Phosphorylation
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
S Phase
Tlk
Tumor Suppressor Proteins
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Summary:All eukaryotes respond to DNA damage by modulation of diverse cellular processes to preserve genomic integrity and ensure survival. Here we identify mammalian Tousled like kinases (Tlks) as a novel target of the DNA damage checkpoint. During S‐phase progression, when Tlks are maximally active, generation of DNA double‐strand breaks (DSBs) leads to rapid and transient inhibition of Tlk activity. Experiments with chemical inhibitors, genetic models and gene targeting through RNA interference demonstrate that this response to DSBs requires ATM and Chk1 function. Chk1 phosphorylates Tlk1 on serine 695 (S695) in vitro , and this UCN‐01‐ and caffeine‐sensitive site is phosphorylated in vivo in response to DNA damage. Substitution of S695 to alanine impaired efficient downregulation of Tlk1 after DNA damage. These findings identify an unprecedented functional co‐ operation between ATM and Chk1 in propagation of a checkpoint response during S phase and suggest that, through transient inhibition of Tlk kinases, the ATM–Chk1–Tlk pathway may regulate processes involved in chromatin assembly.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/cdg151