Article abstract
Nature Cell Biology 9, 391 - 401 (2007)
Published online: 25 March 2007 | doi:10.1038/ncb1555
There is an Erratum (1 June 2007) associated with this article.
HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability
Spencer J. Collis1, Louise J. Barber1, Allison J. Clark1, Julie S. Martin1, Jordan D. Ward1 & Simon J. Boulton1
Abstract
Here, we show that the human homologue of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2) associates with the S-phase checkpoint components ATR, ATRIP, claspin and Chk1. Consistent with a critical role in the S-phase checkpoint, HCLK2-depleted cells accumulate spontaneous DNA damage in S-phase, exhibit radio-resistant DNA synthesis, are impaired for damage-induced monoubiquitination of FANCD2 and fail to recruit FANCD2 and Rad51 (critical components of the Fanconi anaemia and homologous recombination pathways, respectively) to sites of replication stress. Although Thr 68 phosphorylation of the checkpoint effector kinase Chk2 remains intact in the absence of HCLK2, claspin phosphorylation and degradation of the checkpoint phosphatase Cdc25A are compromised following replication stress as a result of accelerated Chk1 degradation. ATR phosphorylation is known to both activate Chk1 and target it for proteolytic degradation, and depleting ATR or mutation of Chk1 at Ser 345 restored Chk1 protein levels in HCLK2-depleted cells. We conclude that HCLK2 promotes activation of the S-phase checkpoint and downstream repair responses by preventing unscheduled Chk1 degradation by the proteasome.
- DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, South Mimms, EN6 3LD, UK
Correspondence to: Simon J. Boulton1 e-mail: simon.boulton@cancer.org.uk
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