DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response

Yu Fen Lin, Hung Ying Shih, Zengfu Shang, Shinji Matsunaga, Benjamin Pc Chen

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The ataxia telangiectasia mutated and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis is the major signaling pathway activated in response to replication stress and is essential for the intra-S checkpoint. ATR phosphorylates and activates a number of molecules to coordinate cell cycle progression. Chk1 is the major effector downstream from ATR and plays a critical role in intra-S checkpoint on replication stress. Activation of Chk1 kinase also requires its association with Claspin, an adaptor protein essential for Chk1 protein stability, recruitment and ATR-dependent Chk1 phosphorylation. We have previously reported that, on replication stress, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is rapidly phosphorylated by ATR at the stalled replication forks and is required for cellular resistance to replication stresses although the impact of DNA-PKcs onto the ATR signaling pathway remains elusive. Here we report that ATR-dependent Chk1 phosphorylation and Chk1 signaling are compromised in the absence of DNA-PKcs. Our investigation reveals that DNA-PKcs is required to maintain Chk1-Claspin complex stability and transcriptional regulation of Claspin expression the impaired Chk1 activity results in a defective intra-S checkpoint response in DNA-PKcs-deficient cells. Taken together, these results suggest that DNA-PKcs, in addition to its direct role in DNA damage repair, facilitates ATR-Chk1 signaling pathway in response to replication stress.

Original languageEnglish (US)
Pages (from-to)4463-4473
Number of pages11
JournalNucleic Acids Research
Volume42
Issue number7
DOIs
StatePublished - 2014

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Ataxia Telangiectasia
DNA
S Phase Cell Cycle Checkpoints
Phosphorylation
Checkpoint Kinase 1
DNA-Activated Protein Kinase
Catalytic DNA
Protein Stability
DNA Repair
DNA Damage
Catalytic Domain
Cell Cycle
Phosphotransferases

ASJC Scopus subject areas

  • Genetics

Cite this

DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response. / Lin, Yu Fen; Shih, Hung Ying; Shang, Zengfu; Matsunaga, Shinji; Chen, Benjamin Pc.

In: Nucleic Acids Research, Vol. 42, No. 7, 2014, p. 4463-4473.

Research output: Contribution to journalArticle

Lin, Yu Fen ; Shih, Hung Ying ; Shang, Zengfu ; Matsunaga, Shinji ; Chen, Benjamin Pc. / DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 7. pp. 4463-4473.
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