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 language | English |
|---|---|
| Pages (from-to) | 134-141 |
| Number of pages | 8 |
| Journal | Cancer Science |
| Volume | 96 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2005 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage
AU - Chen, Ling
AU - Morio, Tomohiro
AU - Minegishi, Yoshiyuki
AU - Nakada, Shin Ichiro
AU - Nagasawa, Masayuki
AU - Komatsu, Kenshi
AU - Chessa, Luciana
AU - Villa, Anna
AU - Lecis, Daniele
AU - Delia, Domenico
AU - Mizutani, Shuki
PY - 2005/2
Y1 - 2005/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=20144370280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20144370280&partnerID=8YFLogxK
U2 - 10.1111/j.1349-7006.2005.00019.x
DO - 10.1111/j.1349-7006.2005.00019.x
M3 - Article
C2 - 15723659
AN - SCOPUS:20144370280
VL - 96
SP - 134
EP - 141
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 2
ER -