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Article ; Online: Sen1 architecture: RNA-DNA hybrid resolution, autoregulation, and insights into SETX inactivation in AOA2.

Appel, C Denise / Bermek, Oya / Dandey, Venkata P / Wood, Makayla / Viverette, Elizabeth / Williams, Jason G / Bouvette, Jonathan / Riccio, Amanda A / Krahn, Juno M / Borgnia, Mario J / Williams, R Scott

Molecular cell

2023 Volume 83, Issue 20, Page(s) 3692–3706.e5

Abstract: The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for Sen1 activities is ill defined. Here, Sen1 cryoelectron ... ...

Abstract	The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for Sen1 activities is ill defined. Here, Sen1 cryoelectron microscopy (cryo-EM) reconstructions reveal an elongated inchworm-like architecture. Sen1 is composed of an amino terminal helical repeat Sen1 N-terminal (Sen1N) regulatory domain that is flexibly linked to its C-terminal SF1B helicase motor core (Sen1
MeSH term(s)	Humans ; RNA/genetics ; Neurodegenerative Diseases ; Cryoelectron Microscopy ; RNA Helicases/genetics ; RNA Helicases/chemistry ; Multifunctional Enzymes/genetics ; DNA/genetics ; Homeostasis ; DNA Helicases/genetics
Chemical Substances	RNA (63231-63-0) ; RNA Helicases (EC 3.6.4.13) ; Multifunctional Enzymes ; DNA (9007-49-2) ; SETX protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2023-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.09.024
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Article ; Online: Structure of the sirtuin-linked macrodomain SAV0325 from Staphylococcus aureus.

Appel, C Denise / Feld, Geoffrey K / Wallace, Bret D / Williams, R Scott

Protein science : a publication of the Protein Society

2016 Volume 25, Issue 9, Page(s) 1682–1691

Abstract: Cells use the post-translational modification ADP-ribosylation to control a host of biological activities. In some pathogenic bacteria, an operon-encoded mono-ADP-ribosylation cycle mediates response to host-induced oxidative stress. In this system, ... ...

Abstract	Cells use the post-translational modification ADP-ribosylation to control a host of biological activities. In some pathogenic bacteria, an operon-encoded mono-ADP-ribosylation cycle mediates response to host-induced oxidative stress. In this system, reversible mono ADP-ribosylation of a lipoylated target protein represses oxidative stress response. An NAD(+) -dependent sirtuin catalyzes the single ADP-ribose (ADPr) addition, while a linked macrodomain-containing protein removes the ADPr. Here we report the crystal structure of the sitruin-linked macrodomain protein from Staphylococcus aureus, SauMacro (also known as SAV0325) to 1.75-Å resolution. The monomeric SauMacro bears a previously unidentified Zn(2+) -binding site that putatively aids in substrate recognition and catalysis. An amino-terminal three-helix bundle motif unique to this class of macrodomain proteins provides a structural scaffold for the Zn(2+) site. Structural features of the enzyme further indicate a cleft proximal to the Zn(2+) binding site appears well suited for ADPr binding, while a deep hydrophobic channel in the protein core is suitable for binding the lipoate of the lipoylated protein target.
MeSH term(s)	Bacterial Proteins/chemistry ; Crystallography, X-Ray ; Protein Domains ; Sirtuins/chemistry ; Staphylococcus aureus/chemistry ; Zinc/chemistry
Chemical Substances	Bacterial Proteins ; Sirtuins (EC 3.5.1.-) ; Zinc (J41CSQ7QDS)
Keywords	covid19
Language	English
Publishing date	2016-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Intramural
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.2974
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Structural features of the guide:target RNA duplex required for archaeal box C/D sRNA-guided nucleotide 2'-O-methylation.

Appel, C Denise / Maxwell, E Stuart

RNA (New York, N.Y.)

2007 Volume 13, Issue 6, Page(s) 899–911

Abstract: Archaeal box C/D sRNAs guide the 2'-O-methylation of target nucleotides using both terminal box C/D and internal C'/D' RNP complexes. In vitro assembly of a catalytically active Methanocaldococcus jannaschii sR8 box C/D RNP provides a model complex to ... ...

Abstract	Archaeal box C/D sRNAs guide the 2'-O-methylation of target nucleotides using both terminal box C/D and internal C'/D' RNP complexes. In vitro assembly of a catalytically active Methanocaldococcus jannaschii sR8 box C/D RNP provides a model complex to determine those structural features of the guide:target RNA duplex important for sRNA-guided nucleotide methylation. Watson-Crick pairing of guide and target nucleotides was found to be essential for methylation, and mismatched bases within the guide:target RNA duplex also disrupted nucleotide modification. However, dependence upon Watson-Crick base-paired guide:target nucleotides for methylation was compromised in elevated Mg(2+) concentrations where mismatched target nucleotides were modified. Nucleotide methylation required that the guide:target duplex consist of an RNA:RNA duplex as a target ribonucleotide within a guide RNA:target DNA duplex that was not methylated. Interestingly, D and D' target RNAs exhibited different levels of methylation when deoxynucleotides were inserted into the target RNA or when target methylation was carried out in elevated Mg(2+) concentrations. These observations suggested that unique structural features of the box C/D and C'/D' RNPs differentially affect their respective methylation capabilities. The ability of the sR8 box C/D sRNP to methylate target nucleotides positioned within highly structured RNA hairpins suggested that the sRNP can facilitate unwinding of double-stranded target RNAs. Finally, increasing target RNA length to extend beyond those nucleotides that base pair with the sRNA guide sequence significantly increased sRNP turnover and thus nucleotide methylation. This suggests that target RNA interaction with the sRNP core proteins is also important for box C/D sRNP-guided nucleotide methylation.
MeSH term(s)	Archaeal Proteins/chemistry ; Archaeal Proteins/genetics ; Archaeal Proteins/metabolism ; Base Pairing ; Base Sequence ; DNA Primers/genetics ; Macromolecular Substances/chemistry ; Macromolecular Substances/metabolism ; Magnesium/metabolism ; Methanococcales/genetics ; Methanococcales/metabolism ; Methylation ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; Nucleotides/chemistry ; Nucleotides/metabolism ; RNA, Archaeal/chemistry ; RNA, Archaeal/genetics ; RNA, Archaeal/metabolism ; Ribonucleoproteins/chemistry ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism ; RNA, Small Untranslated
Chemical Substances	Archaeal Proteins ; DNA Primers ; Macromolecular Substances ; Nucleotides ; RNA, Archaeal ; Ribonucleoproteins ; Magnesium (I38ZP9992A) ; RNA, Small Untranslated
Language	English
Publishing date	2007-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1241540-6
ISSN	1355-8382
ISSN	1355-8382
DOI	10.1261/rna.517307
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Zs.A 4777: Show issues

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Article ; Online: Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2.

Schellenberg, Matthew J / Appel, C Denise / Riccio, Amanda A / Butler, Logan R / Krahn, Juno M / Liebermann, Jenna A / Cortés-Ledesma, Felipe / Williams, R Scott

Nucleic acids research

2020 Volume 48, Issue 11, Page(s) 6310–6325

Abstract: Tyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 ... ...

Abstract	Tyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 functions is unknown. Here, we show that TDP2 co-purifies with K63 and K27 poly-Ubiquitinated cellular proteins independently of, and separately from SUMOylated TOP2 complexes. Poly-ubiquitin chains of ≥ Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA-protein crosslinks in vitro. X-ray crystal structures and small-angle X-ray scattering analysis of TDP2-Ub complexes reveal that the TDP2 UBA domain binds K63-Ub3 in a 1:1 stoichiometric complex that relieves a UBA-regulated autoinhibitory state of TDP2. Our data indicates that that poly-Ub regulates TDP2-catalyzed TOP2-DPC removal, and TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ubiquitin interface.
MeSH term(s)	Binding Sites/genetics ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA Topoisomerases, Type II/metabolism ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Models, Molecular ; Mutation ; Phosphoric Diester Hydrolases/chemistry ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism ; Polyubiquitin/chemistry ; Polyubiquitin/genetics ; Polyubiquitin/metabolism ; Protein Binding ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Substrate Specificity ; Sumoylation ; Ubiquitin/chemistry ; Ubiquitin/genetics ; Ubiquitin/metabolism
Chemical Substances	DNA-Binding Proteins ; SUMO2 protein, human ; Small Ubiquitin-Related Modifier Proteins ; Ubiquitin ; Polyubiquitin (120904-94-1) ; DNA (9007-49-2) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; TDP2 protein, human (EC 3.1.4.-) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
Language	English
Publishing date	2020-05-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa318
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Zs.A 1067: Show issues

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Article ; Online: Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair.

Andres, Sara N / Appel, C Denise / Westmoreland, James W / Williams, Jessica S / Nguyen, Yvonne / Robertson, Patrick D / Resnick, Michael A / Williams, R Scott

Nature structural & molecular biology

2015 Volume 22, Issue 2, Page(s) 158–166

Abstract: Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. We report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and ... ...

Abstract	Ctp1 (also known as CtIP or Sae2) collaborates with Mre11-Rad50-Nbs1 to initiate repair of DNA double-strand breaks (DSBs), but its functions remain enigmatic. We report that tetrameric Schizosaccharomyces pombe Ctp1 contains multivalent DNA-binding and DNA-bridging activities. Through structural and biophysical analyses of the Ctp1 tetramer, we define the salient features of Ctp1 architecture: an N-terminal interlocking tetrameric helical dimer-of-dimers (THDD) domain and a central intrinsically disordered region (IDR) linked to C-terminal 'RHR' DNA-interaction motifs. The THDD, IDR and RHR are required for Ctp1 DNA-bridging activity in vitro, and both the THDD and RHR are required for efficient DSB repair in S. pombe. Our results establish non-nucleolytic roles of Ctp1 in binding and coordination of DSB-repair intermediates and suggest that ablation of human CtIP DNA binding by truncating mutations underlie the CtIP-linked Seckel and Jawad syndromes.
MeSH term(s)	DNA Breaks, Double-Stranded ; DNA Repair/physiology ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Protein Binding ; Protein Multimerization/physiology ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/chemistry ; Schizosaccharomyces pombe Proteins/metabolism
Chemical Substances	Ctp1 protein, S pombe ; DNA-Binding Proteins ; Schizosaccharomyces pombe Proteins
Language	English
Publishing date	2015-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2945
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Zs.A 4101: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Endogenous DNA 3′ Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease

Elsevier Inc. Molecular cell. 2020 June 18, v. 78, no. 6

2020

Abstract: The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective ...

Abstract	The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3′ DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3′-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3′ blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.
Keywords	DNA ; DNA repair ; DNA replication ; cell viability ; death ; enzymes ; genes ; genomics ; neoplasm cells ; neoplasms ; ribonucleotides ; tumor suppressor proteins
Language	English
Dates of publication	2020-0618
Size	p. 1152-1165.e8.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.05.021
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Article ; Online: Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease.

Molecular cell

2020 Volume 78, Issue 6, Page(s) 1152–1165.e8

Abstract	The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3'-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3' blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; Cell Line ; DNA/metabolism ; DNA Damage ; DNA Repair/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Endonucleases/genetics ; Endonucleases/metabolism ; Genes, BRCA1/physiology ; Humans ; Multifunctional Enzymes/genetics ; Multifunctional Enzymes/metabolism ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Multifunctional Enzymes ; DNA (9007-49-2) ; Endonucleases (EC 3.1.-) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; TDP1 protein, human (EC 3.1.4.-) ; APEX1 protein, human (EC 4.2.99.18) ; APEX2 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Language	English
Publishing date	2020-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.05.021
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Article ; Online: Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2.

Schellenberg, Matthew J / Perera, Lalith / Strom, Christina N / Waters, Crystal A / Monian, Brinda / Appel, C Denise / Vilas, Caroline K / Williams, Jason G / Ramsden, Dale A / Williams, R Scott

Nucleic acids research

2016 Volume 44, Issue 8, Page(s) 3829–3844

Abstract: Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular ... ...

Abstract	Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular sensitivity to Top2 poisons. Herein, we report X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA that unveil a dynamic Tdp2 active site lid and deep substrate binding trench well-suited for engaging the diverse DNA damage triggers of abortive Top2 reactions. Modeling of a proposed Tdp2 reaction coordinate, combined with mutagenesis and biochemical studies support a single Mg(2+)-ion mechanism assisted by a phosphotyrosyl-arginine cation-π interface. We further identify a Tdp2 active site SNP that ablates Tdp2 Mg(2+) binding and catalytic activity, impairs Tdp2 mediated NHEJ of tyrosine blocked termini, and renders cells sensitive to the anticancer agent etoposide. Collectively, our results provide a structural mechanism for Tdp2 engagement of heterogeneous DNA damage that causes Top2 poisoning, and indicate that evaluation of Tdp2 status may be an important personalized medicine biomarker informing on individual sensitivities to chemotherapeutic Top2 poisons.
MeSH term(s)	Animals ; Catalytic Domain ; DNA/chemistry ; DNA/metabolism ; DNA Adducts/chemistry ; DNA Adducts/metabolism ; DNA Damage ; DNA End-Joining Repair ; DNA Topoisomerases, Type II/chemistry ; DNA Topoisomerases, Type II/metabolism ; Humans ; Magnesium/chemistry ; Mice ; Mice, Knockout ; Models, Molecular ; Mutation ; Nuclear Proteins/chemistry ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphoric Diester Hydrolases/chemistry ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism ; Phosphotyrosine/metabolism ; Polymorphism, Single Nucleotide ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/chemistry ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism
Chemical Substances	DNA Adducts ; Nuclear Proteins ; Transcription Factors ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ; Phosphotyrosine (21820-51-9) ; DNA (9007-49-2) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; TDP2 protein, human (EC 3.1.4.-) ; TDP2 protein, mouse (EC 3.1.4.-) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2016-04-08
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkw228
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Zs.A 1067: Show issues

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Article ; Online: APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress.

Wallace, Bret D / Berman, Zachary / Mueller, Geoffrey A / Lin, Yunfeng / Chang, Timothy / Andres, Sara N / Wojtaszek, Jessica L / DeRose, Eugene F / Appel, C Denise / London, Robert E / Yan, Shan / Williams, R Scott

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 114, Issue 2, Page(s) 304–309

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 ... ...

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.
MeSH term(s)	Animals ; DNA Damage/genetics ; DNA Glycosylases/metabolism ; DNA Repair/genetics ; DNA Topoisomerases, Type I/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Endonucleases/metabolism ; Oxidative Stress/genetics ; Protein Domains/genetics ; Xenopus laevis/genetics ; Xenopus laevis/metabolism
Chemical Substances	Endonucleases (EC 3.1.-) ; DNA Glycosylases (EC 3.2.2.-) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
Language	English
Publishing date	2016-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1610011114
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Article ; Online: Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2.

Schellenberg, Matthew J / Appel, C Denise / Adhikari, Sanjay / Robertson, Patrick D / Ramsden, Dale A / Williams, R Scott

Nature structural & molecular biology

2012 Volume 19, Issue 12, Page(s) 1363–1371

Abstract: The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA ... ...

Abstract	The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5'-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 β-2-helix-β DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5'-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs.
MeSH term(s)	Animals ; Catalysis ; Crystallography, X-Ray ; DNA Adducts ; DNA Repair ; DNA Topoisomerases, Type II/chemistry ; Mice ; Models, Molecular ; Phosphoric Diester Hydrolases/chemistry
Chemical Substances	DNA Adducts ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; tyrosyl-DNA phosphodiesterase (EC 3.1.4.-) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
Language	English
Publishing date	2012-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2418
Database	MEDical Literature Analysis and Retrieval System OnLINE

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