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Proc Natl Acad Sci U S A
2013 Jun 25;11026:10592-7. doi: 10.1073/pnas.1301445110.
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APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress.
Willis J
,
Patel Y
,
Lentz BL
,
Yan S
.
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The base excision repair pathway is largely responsible for the repair of oxidative stress-induced DNA damage. However, it remains unclear how the DNA damage checkpoint is activated by oxidative stress at the molecular level. Here, we provide evidence showing that hydrogen peroxide (H2O2) triggers checkpoint kinase 1 (Chk1) phosphorylation in an ATR [ataxia-telangiectasia mutated (ATM) and Rad3-related]-dependent but ATM-independent manner in Xenopus egg extracts. A base excision repair protein, Apurinic/apyrimidinic (AP) endonuclease 2 (APE2, APN2, or APEX2), is required for the generation of replication protein A (RPA)-bound single-stranded DNA, the recruitment of a checkpoint protein complex [ATR, ATR-interacting protein (ATRIP), and Rad9] to damage sites, and H2O2-induced Chk1 phosphorylation. A conserved proliferating cell nuclear antigen interaction protein box of APE2 is important for the recruitment of APE2 to H2O2-damaged chromatin. APE2 3'-phosphodiesterase and 3'-5' exonuclease activity is essential for single-stranded DNA generation in the 3'-5' direction from single-stranded breaks, referred to as single-stranded break end resection. In addition, APE2 associates with Chk1, and a serine residue (S86) in the Chk1-binding motif of APE2 is essential for Chk1 phosphorylation, indicating a Claspin-like but distinct role for APE2 in ATR-Chk1 signaling. Our data indicate that APE2 plays a vital and previously unexpected role in ATR-Chk1 checkpoint signaling in response to oxidative stress. Thus, our findings shed light on a distinct mechanism of how an ATR-Chk1-dependent DNA damage checkpoint is mediated by APE2 in the oxidative stress response.
Bakkenist,
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
2003, Pubmed
Bakkenist,
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
2003,
Pubmed
Bartek,
Checking on DNA damage in S phase.
2004,
Pubmed
Boiteux,
Abasic sites in DNA: repair and biological consequences in Saccharomyces cerevisiae.
2004,
Pubmed
Branzei,
Maintaining genome stability at the replication fork.
2010,
Pubmed
Broderick,
Eukaryotic single-stranded DNA binding proteins: central factors in genome stability.
2010,
Pubmed
Brown,
The mismatch repair system is required for S-phase checkpoint activation.
2003,
Pubmed
Burkovics,
Human Ape2 protein has a 3'-5' exonuclease activity that acts preferentially on mismatched base pairs.
2006,
Pubmed
Burkovics,
Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage.
2009,
Pubmed
Byun,
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.
2005,
Pubmed
,
Xenbase
Chang,
Interaction of checkpoint proteins Hus1/Rad1/Rad9 with DNA base excision repair enzyme MutY homolog in fission yeast, Schizosaccharomyces pombe.
2005,
Pubmed
Choi,
Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling.
2010,
Pubmed
Ciccia,
The DNA damage response: making it safe to play with knives.
2010,
Pubmed
Cimprich,
ATR: an essential regulator of genome integrity.
2008,
Pubmed
Costanzo,
An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication.
2003,
Pubmed
,
Xenbase
Daniel,
Loss of ATM kinase activity leads to embryonic lethality in mice.
2012,
Pubmed
David,
Base-excision repair of oxidative DNA damage.
2007,
Pubmed
Eichinger,
9-1-1: PCNA's specialized cousin.
2011,
Pubmed
Fanning,
A dynamic model for replication protein A (RPA) function in DNA processing pathways.
2006,
Pubmed
Friedberg,
DNA damage and repair.
2003,
Pubmed
Friedrich-Heineken,
The two DNA clamps Rad9/Rad1/Hus1 complex and proliferating cell nuclear antigen differentially regulate flap endonuclease 1 activity.
2005,
Pubmed
Gembka,
The checkpoint clamp, Rad9-Rad1-Hus1 complex, preferentially stimulates the activity of apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta in long patch base excision repair.
2007,
Pubmed
Giannattasio,
Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation.
2010,
Pubmed
Guan,
The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase.
2007,
Pubmed
Guo,
ATM activation by oxidative stress.
2010,
Pubmed
Guo,
Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Hadi,
Second human protein with homology to the Escherichia coli abasic endonuclease exonuclease III.
2000,
Pubmed
Hamdan,
Motors, switches, and contacts in the replisome.
2009,
Pubmed
Handa,
Reconstitution of initial steps of dsDNA break repair by the RecF pathway of E. coli.
2009,
Pubmed
Harper,
The DNA damage response: ten years after.
2007,
Pubmed
Harrison,
Surviving the breakup: the DNA damage checkpoint.
2006,
Pubmed
Hegde,
Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells.
2008,
Pubmed
Hickson,
Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.
2004,
Pubmed
Kelch,
How a DNA polymerase clamp loader opens a sliding clamp.
2011,
Pubmed
Kim,
Overview of base excision repair biochemistry.
2012,
Pubmed
Klaunig,
Oxidative stress and oxidative damage in carcinogenesis.
2010,
Pubmed
Kulkarni,
Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation.
2008,
Pubmed
Kumagai,
Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1.
2003,
Pubmed
,
Xenbase
Kumagai,
Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1.
2004,
Pubmed
,
Xenbase
Kumagai,
Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Lee,
ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.
2005,
Pubmed
Lyubimov,
ATP-dependent conformational dynamics underlie the functional asymmetry of the replicative helicase from a minimalist eukaryote.
2012,
Pubmed
Meira,
Base excision repair.
2005,
Pubmed
Moldovan,
PCNA, the maestro of the replication fork.
2007,
Pubmed
Navadgi-Patil,
A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1.
2009,
Pubmed
Odell,
Rules of engagement for base excision repair in chromatin.
2013,
Pubmed
Olson,
RPA2 is a direct downstream target for ATR to regulate the S-phase checkpoint.
2006,
Pubmed
Parrilla-Castellar,
Dial 9-1-1 for DNA damage: the Rad9-Hus1-Rad1 (9-1-1) clamp complex.
2004,
Pubmed
Polo,
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.
2011,
Pubmed
Sancar,
Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
2004,
Pubmed
Sarkaria,
Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
1999,
Pubmed
Shackelford,
The Ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts.
2001,
Pubmed
Shevelev,
The 3' 5' exonucleases.
2002,
Pubmed
Shiotani,
Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks.
2009,
Pubmed
Smirnova,
The human checkpoint sensor and alternative DNA clamp Rad9-Rad1-Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery.
2005,
Pubmed
Symington,
Double-strand break end resection and repair pathway choice.
2011,
Pubmed
Tell,
The many functions of APE1/Ref-1: not only a DNA repair enzyme.
2009,
Pubmed
Tsuchimoto,
Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen.
2001,
Pubmed
Tutter,
Chromosomal DNA replication in a soluble cell-free system derived from Xenopus eggs.
2006,
Pubmed
,
Xenbase
Unk,
Stimulation of 3'-->5' exonuclease and 3'-phosphodiesterase activities of yeast apn2 by proliferating cell nuclear antigen.
2002,
Pubmed
Unk,
3'-phosphodiesterase and 3'-->5' exonuclease activities of yeast Apn2 protein and requirement of these activities for repair of oxidative DNA damage.
2001,
Pubmed
Van,
Continued primer synthesis at stalled replication forks contributes to checkpoint activation.
2010,
Pubmed
,
Xenbase
Wang,
Mechanism of stimulation of human DNA ligase I by the Rad9-rad1-Hus1 checkpoint complex.
2006,
Pubmed
Wang,
Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing.
2011,
Pubmed
Willis,
Study of the DNA damage checkpoint using Xenopus egg extracts.
2012,
Pubmed
,
Xenbase
Wold,
Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism.
1997,
Pubmed
Xie,
Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3.
2001,
Pubmed
Yan,
Direct requirement for Xmus101 in ATR-mediated phosphorylation of Claspin bound Chk1 during checkpoint signaling.
2006,
Pubmed
,
Xenbase
Yan,
TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks.
2009,
Pubmed
,
Xenbase
Yan,
WD40-repeat protein WDR18 collaborates with TopBP1 to facilitate DNA damage checkpoint signaling.
2013,
Pubmed
,
Xenbase
Yoo,
Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures.
2006,
Pubmed
,
Xenbase
Yoshioka,
ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts.
2006,
Pubmed
Zhao,
ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.
2001,
Pubmed
Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
