Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

Song Zhao, Yi Chinn Wong, Shyng Shlou F Yuan, Yi Tzu Lin, Hao Chi Hsu, Suh Chin J Lin, Elvira Gerbino, Mel Hua Song, Malgorzata Z. Zdzlenlcka, Richard A. Gatti, Jerry W. Shay, Yael Ziv, Yosef Shilch, Eva Y H P Lee

Research output: Contribution to journalArticle

418 Citations (Scopus)

Abstract

Ataxia telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre11. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

Original languageEnglish (US)
Pages (from-to)473-477
Number of pages5
JournalNature
Volume405
Issue number6785
DOIs
StatePublished - May 25 2000

Fingerprint

Nijmegen Breakage Syndrome
Ataxia Telangiectasia
Ionizing Radiation
Inborn Genetic Diseases
DNA Repair
DNA Damage
S Phase Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinase
Genes
Phenotype
Proteins
Cell Cycle Checkpoints
Hypersensitivity
Phosphotransferases
Phosphorylation
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Zhao, S., Wong, Y. C., Yuan, S. S. F., Lin, Y. T., Hsu, H. C., Lin, S. C. J., ... Lee, E. Y. H. P. (2000). Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature, 405(6785), 473-477. https://doi.org/10.1038/35013083

Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. / Zhao, Song; Wong, Yi Chinn; Yuan, Shyng Shlou F; Lin, Yi Tzu; Hsu, Hao Chi; Lin, Suh Chin J; Gerbino, Elvira; Song, Mel Hua; Zdzlenlcka, Malgorzata Z.; Gatti, Richard A.; Shay, Jerry W.; Ziv, Yael; Shilch, Yosef; Lee, Eva Y H P.

In: Nature, Vol. 405, No. 6785, 25.05.2000, p. 473-477.

Research output: Contribution to journalArticle

Zhao, S, Wong, YC, Yuan, SSF, Lin, YT, Hsu, HC, Lin, SCJ, Gerbino, E, Song, MH, Zdzlenlcka, MZ, Gatti, RA, Shay, JW, Ziv, Y, Shilch, Y & Lee, EYHP 2000, 'Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products', Nature, vol. 405, no. 6785, pp. 473-477. https://doi.org/10.1038/35013083
Zhao S, Wong YC, Yuan SSF, Lin YT, Hsu HC, Lin SCJ et al. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature. 2000 May 25;405(6785):473-477. https://doi.org/10.1038/35013083
Zhao, Song ; Wong, Yi Chinn ; Yuan, Shyng Shlou F ; Lin, Yi Tzu ; Hsu, Hao Chi ; Lin, Suh Chin J ; Gerbino, Elvira ; Song, Mel Hua ; Zdzlenlcka, Malgorzata Z. ; Gatti, Richard A. ; Shay, Jerry W. ; Ziv, Yael ; Shilch, Yosef ; Lee, Eva Y H P. / Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. In: Nature. 2000 ; Vol. 405, No. 6785. pp. 473-477.
@article{3ff1efcd1b8448b9a0348cd20347cdda,
title = "Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products",
abstract = "Ataxia telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre11. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.",
author = "Song Zhao and Wong, {Yi Chinn} and Yuan, {Shyng Shlou F} and Lin, {Yi Tzu} and Hsu, {Hao Chi} and Lin, {Suh Chin J} and Elvira Gerbino and Song, {Mel Hua} and Zdzlenlcka, {Malgorzata Z.} and Gatti, {Richard A.} and Shay, {Jerry W.} and Yael Ziv and Yosef Shilch and Lee, {Eva Y H P}",
year = "2000",
month = "5",
day = "25",
doi = "10.1038/35013083",
language = "English (US)",
volume = "405",
pages = "473--477",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6785",

}

TY - JOUR

T1 - Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

AU - Zhao, Song

AU - Wong, Yi Chinn

AU - Yuan, Shyng Shlou F

AU - Lin, Yi Tzu

AU - Hsu, Hao Chi

AU - Lin, Suh Chin J

AU - Gerbino, Elvira

AU - Song, Mel Hua

AU - Zdzlenlcka, Malgorzata Z.

AU - Gatti, Richard A.

AU - Shay, Jerry W.

AU - Ziv, Yael

AU - Shilch, Yosef

AU - Lee, Eva Y H P

PY - 2000/5/25

Y1 - 2000/5/25

N2 - Ataxia telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre11. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

AB - Ataxia telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre11. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

UR - http://www.scopus.com/inward/record.url?scp=0034713393&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034713393&partnerID=8YFLogxK

U2 - 10.1038/35013083

DO - 10.1038/35013083

M3 - Article

C2 - 10839544

AN - SCOPUS:0034713393

VL - 405

SP - 473

EP - 477

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6785

ER -