Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage

Ling Chen, Tomohiro Morio, Yoshiyuki Minegishi, Shin Ichiro Nakada, Masayuki Nagasawa, Kenshi Komatsu, Luciana Chessa, Anna Villa, Daniele Lecis, Domenico Delia, Shuki Mizutani

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs). A defect in Artemis causes human radiosensitive-severe combined immunodeficiency. Cells from Artemis-deficient patients and mice display increased chromosomal instability, but the precise function of this factor in the response to DNA damage remains to be elucidate. In this study, we show that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)- and Nijmegen breakage syndrome 1 (Nbs1)-dependent manner in response to ionizing radiation (IR), and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. The hyperphosphorylation of Artemis is markedly reduced in ATM- and Nbs1-null cells. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in ATM- or Nbs1-deficient cells, respectively. In support of this functional link, hyperphosphorylated Artemis was found to physically associate with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DNA double strand breaks (DSB). Since deficiency of either DNA-Pkcs or ATM leads to defective repair of IR-induced DSB, our finding places Artemis at the signaling crossroads downstream of DNA-PKcs and ATM in IR-induced DSB repair.

Original languageEnglish
Pages (from-to)134-141
Number of pages8
JournalCancer Science
Volume96
Issue number2
DOIs
Publication statusPublished - Feb 2005

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Ataxia Telangiectasia
Nijmegen Breakage Syndrome
Phosphorylation
Ionizing Radiation
DNA
V(D)J Recombination
Severe Combined Immunodeficiency
Null Lymphocytes
Chromosomal Instability
Antigen Receptors
Protein Kinases
Catalytic Domain
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chen, L., Morio, T., Minegishi, Y., Nakada, S. I., Nagasawa, M., Komatsu, K., ... Mizutani, S. (2005). Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Cancer Science, 96(2), 134-141. https://doi.org/10.1111/j.1349-7006.2005.00019.x

Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. / Chen, Ling; Morio, Tomohiro; Minegishi, Yoshiyuki; Nakada, Shin Ichiro; Nagasawa, Masayuki; Komatsu, Kenshi; Chessa, Luciana; Villa, Anna; Lecis, Daniele; Delia, Domenico; Mizutani, Shuki.

In: Cancer Science, Vol. 96, No. 2, 02.2005, p. 134-141.

Research output: Contribution to journalArticle

Chen, L, Morio, T, Minegishi, Y, Nakada, SI, Nagasawa, M, Komatsu, K, Chessa, L, Villa, A, Lecis, D, Delia, D & Mizutani, S 2005, 'Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage', Cancer Science, vol. 96, no. 2, pp. 134-141. https://doi.org/10.1111/j.1349-7006.2005.00019.x
Chen, Ling ; Morio, Tomohiro ; Minegishi, Yoshiyuki ; Nakada, Shin Ichiro ; Nagasawa, Masayuki ; Komatsu, Kenshi ; Chessa, Luciana ; Villa, Anna ; Lecis, Daniele ; Delia, Domenico ; Mizutani, Shuki. / Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. In: Cancer Science. 2005 ; Vol. 96, No. 2. pp. 134-141.
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