uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint
Show others and affiliations
2003 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 22, no 7, 1676-1687 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2003. Vol. 22, no 7, 1676-1687 p.
Keyword [en]
Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Primers, DNA-Binding Proteins, Humans, Mutagenesis; Site-Directed, Phosphorylation, Protein Kinases/*metabolism, Protein-Serine-Threonine Kinases/antagonists & inhibitors/*metabolism, S Phase, Tumor Suppressor Proteins
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-10503DOI: 10.1093/emboj/cdg151PubMedID: 12660173OAI: oai:DiVA.org:uu-10503DiVA: diva2:38271
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2013-10-30Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12660173&dopt=Citation

Search in DiVA

By author/editor
Wernstedt, Christer
By organisation
Ludwig Institute for Cancer Research
In the same journal
EMBO Journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 196 hits
ReferencesLink to record
Permanent link

Direct link