PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway

Yu Fen Lin, Hung Ying Shih, Zeng Fu Shang, Ching Te Kuo, Jiaming Guo, Chunying Du, Hsinyu Lee, Benjamin P.C. Chen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The DNA-dependent protein kinase (DNA-PK), consisting of the DNA binding Ku70/80 heterodimer and the catalytic subunit DNA-PKcs, has been well characterized in the non-homologous end-joining mechanism for DNA double strand break (DSB) repair and radiation resistance. Besides playing a role in DSB repair, DNA-PKcs is required for the cellular response to replication stress and participates in the ATR-Chk1 signaling pathway. However, the mechanism through which DNA-PKcs is recruited to stalled replication forks is still unclear. Here, we report that the apoptosis mediator p53-induced protein with a death domain (PIDD) is required to promote DNAPKcs activity in response to replication stress. PIDD is known to interact with PCNA upon UV-induced replication stress. Our results demonstrate that PIDD is required to recruit DNA-PKcs to stalled replication forks through direct binding to DNA-PKcs at the N' terminal region. Disruption of the interaction between DNA-PKcs and PIDD not only compromises the ATR association and regulation of DNA-PKcs, but also the ATR signaling pathway, intra-S-phase checkpoint and cellular resistance to replication stress. Taken together, our results indicate that PIDD, but not the Ku heterodimer, mediates the DNA-PKcs activity at stalled replication forks and facilitates the ATR signaling pathway in the cellular response to replication stress.

Original languageEnglish (US)
Pages (from-to)1847-1859
Number of pages13
JournalNucleic Acids Research
Volume46
Issue number4
DOIs
StatePublished - Feb 28 2018

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DNA
S Phase Cell Cycle Checkpoints
Proteins
DNA End-Joining Repair
DNA-Activated Protein Kinase
Catalytic DNA
Double-Stranded DNA Breaks
Proliferating Cell Nuclear Antigen
Death Domain
Catalytic Domain
Radiation
Apoptosis

ASJC Scopus subject areas

  • Genetics

Cite this

PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway. / Lin, Yu Fen; Shih, Hung Ying; Shang, Zeng Fu; Kuo, Ching Te; Guo, Jiaming; Du, Chunying; Lee, Hsinyu; Chen, Benjamin P.C.

In: Nucleic Acids Research, Vol. 46, No. 4, 28.02.2018, p. 1847-1859.

Research output: Contribution to journalArticle

Lin, Yu Fen ; Shih, Hung Ying ; Shang, Zeng Fu ; Kuo, Ching Te ; Guo, Jiaming ; Du, Chunying ; Lee, Hsinyu ; Chen, Benjamin P.C. / PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 4. pp. 1847-1859.
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