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

TY - JOUR

T1 - Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint.

AU - Groth, Anja

AU - Lukas, Jiri

AU - Nigg, Erich A

AU - Silljé, Herman H W

AU - Wernstedt, Christer

AU - Bartek, Jiri

AU - Hansen, Klaus

N1 - Keywords: Base Sequence; Cell Cycle Proteins; Cell Line; DNA Damage; DNA Primers; DNA-Binding Proteins; Humans; Mutagenesis, Site-Directed; Phosphorylation; Protein Kinases; Protein-Serine-Threonine Kinases; S Phase; Tumor Suppressor Proteins

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

U2 - 10.1093/emboj/cdg151

DO - 10.1093/emboj/cdg151

M3 - Journal article

C2 - 12660173

SN - 0261-4189

VL - 22

SP - 1676

EP - 1687

JO - EMBO Journal

JF - EMBO Journal

IS - 7

ER -