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PMID: 15456891 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response.

Molecular and cellular biology ·Vol. 24 ·No. 20 ·2004-10-00 ·Pages 9207-20

Zhang X, Succi J, Feng Z, Prithivirajsingh S, Story MD, Legerski RJ

Abstract

Mutations in Artemis in both humans and mice result in severe combined immunodeficiency due to a defect in V(D)J recombination. In addition, Artemis mutants are radiosensitive and chromosomally unstable, which has been attributed to a defect in nonhomologous end joining (NHEJ). We show here, however, that Artemis-depleted cell extracts are not defective in NHEJ and that Artemis-deficient cells have normal repair kinetics of double-strand breaks after exposure to ionizing radiation (IR). Artemis is shown, however, to interact with known cell cycle checkpoint proteins and to be a phosphorylation target of the checkpoint kinase ATM or ATR after exposure of cells to IR or UV irradiation, respectively. Consistent with these findings, our results also show that Artemis is required for the maintenance of a normal DNA damage-induced G2/M cell cycle arrest. Artemis does not appear, however, to act either upstream or downstream of checkpoint kinase Chk1 or Chk2. These results define Artemis as having a checkpoint function and suggest that the radiosensitivity and chromosomal instability of Artemis-deficient cells may be due to defects in cell cycle responses after DNA damage.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/genetics,metabolism Cell Division/physiology Checkpoint Kinase 1 Checkpoint Kinase 2 Chromosomal Instability/physiology,radiation effects DNA/metabolism,radiation effects DNA Damage DNA Repair DNA-Activated Protein Kinase DNA-Binding Proteins/metabolism Endonucleases G2 Phase/physiology Humans Mice Nuclear Proteins/genetics,metabolism Phosphorylation Protein Kinases/metabolism Protein Serine-Threonine Kinases/genetics,metabolism RNA, Small Interfering/genetics,metabolism Radiation, Ionizing Recombinant Fusion Proteins/genetics,metabolism Tumor Suppressor Proteins Ultraviolet Rays
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Nuclear Proteins RNA, Small Interfering Recombinant Fusion Proteins Tumor Suppressor Proteins DNA Protein Kinases Checkpoint Kinase 2 ATM protein, human ATR protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse CHEK1 protein, human CHEK2 protein, human Checkpoint Kinase 1 Chek1 protein, mouse Chek2 protein, mouse DNA-Activated Protein Kinase PRKDC protein, human Protein Serine-Threonine Kinases DCLRE1C protein, human Endonucleases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zhang Xiaoshan
Department of Molecular Genetics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Succi Janice
Feng Zhaohui
Prithivirajsingh Sheela
Story Michael D
Legerski Randy J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.20.9207-9220.2004
Published
2004-10-00
Pages
9207-20
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC517881
Subset
IM
Grants
NCI NIH HHS · CA96574 · United States
NCI NIH HHS · CA90270 · United States
NCI NIH HHS · P50 CA090270 · United States
NCI NIH HHS · CA52461 · United States
NCI NIH HHS · R01 CA052461 · United States
NCI NIH HHS · R01 CA096574 · United States
NIEHS NIH HHS · P30 ES007784 · United States
NIEHS NIH HHS · ES07784 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.20.9207-9220.2004 PMC Full Text View journal details
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