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The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage

Oncogene volume 29, pages 1431–1450 (2010)Cite this article

Abstract

The p53-inducible gene 3 (PIG3) is originally isolated as a p53 downstream target gene, but its function remains unknown. Here, we report a role of PIG3 in the activation of DNA damage checkpoints, after UV irradiation or radiomimetic drug neocarzinostatin (NCS). We show that depletion of endogenous PIG3 sensitizes cells to DNA damage agents, and impaired DNA repair. PIG3 depletion also allows for UV- and NCS-resistant DNA synthesis and permits cells to progress into mitosis, indicating that PIG3 knockdown can suppress intra-S phase and G2/M checkpoints. PIG3-depleted cells show reduced Chk1 and Chk2 phosphorylation after DNA damage, which may directly contribute to checkpoint bypass. PIG3 exhibited diffuse nuclear staining in the majority of untreated cells and forms discrete nuclear foci in response to DNA damage. PIG3 colocalizes with γ-H2AX and 53BP1 to sites of DNA damage after DNA damage, and binds to a γ-H2AX. Notably, PIG3 depletion decreases the efficient induction and maintenance of H2AX phosphorylation after DNA damage. Moreover, PIG3 contributes to the recruitment of 53BP1, Mre11, Rad50 and Nbs1 to the sites of DNA break lesions in response to DNA damage. Our combined results suggest that PIG3 is a critical component of the DNA damage response pathway and has a direct role in the transmission of the DNA damage signal from damaged DNA to the intra-S and G2/M checkpoint machinery in human cells.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ATM:

ataxia telangiectasia mutated

ATR:

ATM and Rad3 related

53BP1:

p53-binding protein

DNA-PK:

DNA-dependent protein kinases

DSBs:

double-strand breaks

NCS:

neocarzinostatin

PIG3:

p53-inducible gene 3

PIKK:

phosphatidylinositol 3-kinase-like kinase

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Acknowledgements

This research was supported by grants (M 2009-0065519 and M 20706000032) from the Ministry of Education, Science and Technology, the Korean government and from the Chosun University, 2002.

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Authors and Affiliations

  1. Department of Bio-materials, DNA Repair Research Center, Chosun University, Gwangju, Republic of Korea

    J-H Lee, Y Kang, V Khare, Z-Y Jin, M-Y Kang, Y Yoon & H J You

  2. Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea

    J-H Lee, Y Kang, M-Y Kang, Y Yoon & H J You

  3. Department of Biochemistry, School of Medicine, Cheju National University, Jeju-si, Republic of Korea

    J-W Hyun

  4. Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea

    M-H Chung

  5. Department of Otorhinolaryngology, Chosun University School of Medicine, Gwangju, Republic of Korea

    S-I Cho

  6. Department of Physiology, Chosun University School of Medicine, Gwangju, Republic of Korea

    J Y Jun

  7. Department of Anatomy, Chosun University School of Medicine, Gwangju, Republic of Korea

    I-Y Chang

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  1. J-H Lee
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Correspondence to H J You.

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Lee, JH., Kang, Y., Khare, V. et al. The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage. Oncogene 29, 1431–1450 (2010). https://doi.org/10.1038/onc.2009.438

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