Single-stranded DNA induces ataxia telangiectasia mutant (ATM)/p53-dependent DNA damage and apoptotic signals.
Single-stranded DNA has been speculated to be the initial signal in the DNA damage signaling pathway. We showed that introduction of single-stranded DNA with diverse sequences into mammalian cells induced DNA damage as well as apoptosis signals. Like DNA damaging agents, single-stranded DNA up-regulated p53 and activated the nuclear kinase ataxia telangiectasia mutant (ATM) as evidenced by phosphorylation of histone 2AX, an endogenous ATM substrate. Single-stranded DNA also triggered apoptosis as evidenced by the formation of caspase-dependent chromosomal DNA strand breaks, cytochrome c release, and increase in reactive oxygen species production. Moreover, single-stranded DNA-induced apoptosis was reduced significantly in p53 null cells and in cells treated with ATM small interfering RNA. These results suggest that single-stranded DNA may act upstream of ATM/p53 in DNA damage signaling.
Nur-E-Kamal
Alam
A
Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA. nurekasa@umdnj.edu
Li
Tsai-Kun
TK
Zhang
Ailing
A
Qi
Haiyan
H
Hars
Eszter S
ES
Liu
Leroy F
LF
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D015415:Biomarkers; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000502:physiology*; D004277:DNA, Single-Stranded / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D003851:Deoxyribonucleases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009841:Oligonucleotides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D015415:Biomarkers; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D003851:Deoxyribonucleases