Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2017 Jan 10;1142:304-309. doi: 10.1073/pnas.1610011114.
Show Gene links
Show Anatomy links
APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress.
Wallace BD
,
Berman Z
,
Mueller GA
,
Lin Y
,
Chang T
,
Andres SN
,
Wojtaszek JL
,
DeRose EF
,
Appel CD
,
London RE
,
Yan S
,
Williams RS
.
???displayArticle.abstract???
The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3'-5' nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3'-5' exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.
Andres,
Recognition and repair of chemically heterogeneous structures at DNA ends.
2015, Pubmed
Andres,
Recognition and repair of chemically heterogeneous structures at DNA ends.
2015,
Pubmed
Bakkenist,
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
2003,
Pubmed
Bandaru,
A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII.
2002,
Pubmed
Bartek,
Checking on DNA damage in S phase.
2004,
Pubmed
Baute,
Base excision repair and its role in maintaining genome stability.
2008,
Pubmed
Boiteux,
Abasic sites in DNA: repair and biological consequences in Saccharomyces cerevisiae.
2004,
Pubmed
Brown,
Zinc finger proteins: getting a grip on RNA.
2005,
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
Chen,
Chk1 in the DNA damage response: conserved roles from yeasts to mammals.
2004,
Pubmed
Cheung,
Structural basis of RNA polymerase II backtracking, arrest and reactivation.
2011,
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
Delacroix,
The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1.
2007,
Pubmed
Gamsjaeger,
Sticky fingers: zinc-fingers as protein-recognition motifs.
2007,
Pubmed
Grishin,
C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily.
2000,
Pubmed
Guikema,
Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge.
2011,
Pubmed
Hadi,
Second human protein with homology to the Escherichia coli abasic endonuclease exonuclease III.
2000,
Pubmed
Hadi,
Determinants in nuclease specificity of Ape1 and Ape2, human homologues of Escherichia coli exonuclease III.
2002,
Pubmed
Harrison,
Surviving the breakup: the DNA damage checkpoint.
2006,
Pubmed
Hegde,
Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases.
2012,
Pubmed
Ide,
Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice.
2004,
Pubmed
Jackson,
The DNA-damage response in human biology and disease.
2009,
Pubmed
Jin,
Interaction of apurinic/apyrimidinic endonuclease 2 (Apn2) with Myh1 DNA glycosylase in fission yeast.
2014,
Pubmed
Johnson,
Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites.
1998,
Pubmed
Jones,
Redefining oxidative stress.
2006,
Pubmed
Klug,
Zinc finger peptides for the regulation of gene expression.
1999,
Pubmed
Krokan,
Base excision repair.
2013,
Pubmed
Kumagai,
TopBP1 activates the ATR-ATRIP complex.
2006,
Pubmed
,
Xenbase
Lee,
ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.
2005,
Pubmed
Lee,
AP endonucleases process 5-methylcytosine excision intermediates during active DNA demethylation in Arabidopsis.
2014,
Pubmed
Matsuoka,
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
2007,
Pubmed
Matthews,
Zinc fingers--folds for many occasions.
2002,
Pubmed
Oates,
D²P²: database of disordered protein predictions.
2013,
Pubmed
Putnam,
Protein mimicry of DNA and pathway regulation.
2005,
Pubmed
Putnam,
Protein mimicry of DNA from crystal structures of the uracil-DNA glycosylase inhibitor protein and its complex with Escherichia coli uracil-DNA glycosylase.
1999,
Pubmed
Qian,
Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS.
1993,
Pubmed
Rass,
Actions of aprataxin in multiple DNA repair pathways.
2007,
Pubmed
Richardson,
Oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells.
2015,
Pubmed
Sepúlveda,
Expression, functionality, and localization of apurinic/apyrimidinic endonucleases in replicative and non-replicative forms of Trypanosoma cruzi.
2014,
Pubmed
Stavnezer,
Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation.
2014,
Pubmed
Tell,
The many functions of APE1/Ref-1: not only a DNA repair enzyme.
2009,
Pubmed
Thanan,
Oxidative stress and its significant roles in neurodegenerative diseases and cancer.
2014,
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
Tumbale,
Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease.
2011,
Pubmed
Tumbale,
Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity.
2014,
Pubmed
Unk,
Stimulation of 3'-->5' exonuclease and 3'-phosphodiesterase activities of yeast apn2 by proliferating cell nuclear antigen.
2002,
Pubmed
Unk,
Apurinic endonuclease activity of yeast Apn2 protein.
2000,
Pubmed
Willis,
Study of the DNA damage checkpoint using Xenopus egg extracts.
2012,
Pubmed
,
Xenbase
Willis,
APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress.
2013,
Pubmed
,
Xenbase
Wilson,
The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA.
2001,
Pubmed
Yan,
Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress.
2014,
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
Zeman,
Causes and consequences of replication stress.
2014,
Pubmed
Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
