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PMID: 18599436 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Complementary functions of ATM and H2AX in development and suppression of genomic instability.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 27 ·2008-07-08 ·Pages 9302-6

Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW

Abstract

Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM/H2AX deficiency caused embryonic lethality and dramatic cellular genomic instability. Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency. We discuss these findings in the context of synergies between ATM and other repair factors.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/metabolism Cell Proliferation DNA Damage DNA Repair DNA-Binding Proteins/metabolism Embryo Loss/metabolism Embryo, Mammalian/abnormalities,metabolism Embryonic Stem Cells/metabolism Female Fibroblasts/metabolism,pathology Genomic Instability Histones/metabolism Mice Pregnancy Protein Serine-Threonine Kinases/metabolism Reactive Oxygen Species/metabolism Tumor Suppressor Proteins/metabolism
Chemicals
Cell Cycle Proteins DNA-Binding Proteins H2AX protein, mouse Histones Reactive Oxygen Species Tumor Suppressor Proteins Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zha Shan
Howard Hughes Medical Institute, Children's Hospital, Immune Disease Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Sekiguchi JoAnn
Brush James W
Bassing Craig H
Alt Frederick W
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0803520105
Published
2008-07-08
Epub
2008-00-01
Pages
9302-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2453730
Subset
IM
Grants
NCI NIH HHS · 5R01 CA125195-02 · United States
NCI NIH HHS · P01 CA109901 · United States
NCI NIH HHS · 5P01 CA92625-06 · United States
NCI NIH HHS · R01 CA125195 · United States
NCI NIH HHS · 5P01 CA109901-03 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P01 CA092625 · United States
NCI NIH HHS · R01 CA125195-02 · United States
NCI NIH HHS · 5P01CA92625-06 · United States
External Links
PubMed source DOI: 10.1073/pnas.0803520105 PMC Full Text View journal details
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