Complementary functions of ATM and H2AX in development and suppression of genomic instability.
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.
Zha
Shan
S
Howard Hughes Medical Institute, Children's Hospital, Immune Disease Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Sekiguchi
JoAnn
J
Brush
James W
JW
Bassing
Craig H
CH
Alt
Frederick W
FW
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020964:Embryo Loss / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C576325:Atm protein, mouse; C475961:gamma-H2AX protein, mouse