Structural basis for $\mathrm{APE1}$ processing $\mathrm{DNA}$ damage in the nucleosome

Weaver, Tyler M.; Hoitsma, Nicole M.; Spencer, Jonah J.; Gakhar, Lokesh; Schnicker, Nicholas J.; Freudenthal, Bret D.

doi:10.1038/s41467-022-33057-7

Structural basis for $$\mathrm{APE1}$$ processing $$\mathrm{DNA}$$ damage in the nucleosome

Journal Article · Wed Sep 14 00:00:00 EDT 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-33057-7· OSTI ID:1903927

Weaver, Tyler M. ^[1]; Hoitsma, Nicole M. ^[2]; Spencer, Jonah J. ^[2]; ^[3]; ^[3]; ^[4]

University of Kansas Medical Center, Kansas City, KS (United States); OSTI
University of Kansas Medical Center, Kansas City, KS (United States)
University of Iowa Carver College of Medicine, Iowa City, IA (United States)
University of Kansas Medical Center, Kansas City, KS (United States); University of Kansas Cancer Center, Kansas City, KS (United States)

Genomic DNA is continually exposed to endogenous and exogenous factors that promote DNA damage. Eukaryotic genomic DNA is packaged into nucleosomes, which present a barrier to accessing and effectively repairing DNA damage. The mechanisms by which DNA repair proteins overcome this barrier to repair DNA damage in the nucleosome and protect genomic stability is unknown. Here, we determine how the base excision repair (BER) endonuclease AP-endonuclease 1 (APE1) recognizes and cleaves DNA damage in the nucleosome. Kinetic assays determine that APE1 cleaves solvent-exposed AP sites in the nucleosome with 3-6 orders of magnitude higher efficiency than occluded AP sites. A cryo-electron microscopy structure of APE1 bound to a nucleosome containing a solvent-exposed AP site reveal that APE1 uses a DNA sculpting mechanism for AP site recognition, where APE1 bends the nucleosomal DNA to access the AP site. Notably, additional biochemical and structural characterization of occluded AP sites identify contacts between the nucleosomal DNA and histone octamer that prevent efficient processing of the AP site by APE1. These findings provide a rationale for the position-dependent activity of BER proteins in the nucleosome and suggests the ability of BER proteins to sculpt nucleosomal DNA drives efficient BER in chromatin.

View Accepted Manuscript (DOE)

Research Organization:: University of Kansas Medical Center, Kansas City, KS (United States)

Sponsoring Organization:: National Cancer Institute; National Institute of General Medical Science; National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903927

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (62)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
UCSF ChimeraX: Meeting modern challenges in visualization and analysis: UCSF ChimeraX Visualization System Goddard, Thomas D.; Huang, Conrad C.; Meng, Elaine C. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3235	journal	September 2017
The role of Mg2+ and specific amino acid residues in the catalytic reaction of the major human abasic endonuclease: new insights from EDTA-resistant incision of acyclic abasic site analogs and site-directed mutagenesis Erzberger, Jan P.; Wilson, David M. Journal of Molecular Biology, Vol. 290, Issue 2 https://doi.org/10.1006/jmbi.1999.2888	journal	July 1999
Mapping the protein-DNA interface and the metal-binding site of the major human apurinic/apyrimidinic endonuclease Nguyen, Lam H.; Barsky, Daniel; Erzberger, Jan P. Journal of Molecular Biology, Vol. 298, Issue 3 https://doi.org/10.1006/jmbi.2000.3653	journal	May 2000
The abasic site as a challenge to DNA polymerase Cuniasse, Ph.; Fazakerley, G. V.; Guschlbauer, W. Journal of Molecular Biology, Vol. 213, Issue 2 https://doi.org/10.1016/S0022-2836(05)80192-5	journal	May 1990
Reconstitution of Nucleosome Core Particles from Recombinant Histones and DNA Dyer, Pamela N.; Edayathumangalam, Raji S.; White, Cindy L. Chromatin and Chromatin Remodeling Enzymes, Part A https://doi.org/10.1016/S0076-6879(03)75002-2	book	January 2003
Recent advances in the structural mechanisms of DNA glycosylases Brooks, Sonja C.; Adhikary, Suraj; Rubinson, Emily H. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 1 https://doi.org/10.1016/j.bbapap.2012.10.005	journal	January 2013
Somatic and Germline Mutation Periodicity Follow the Orientation of the DNA Minor Groove around Nucleosomes Pich, Oriol; Muiños, Ferran; Sabarinathan, Radhakrishnan Cell, Vol. 175, Issue 4 https://doi.org/10.1016/j.cell.2018.10.004	journal	November 2018
Human OGG1 activity in nucleosomes is facilitated by transient unwrapping of DNA and is influenced by the local histone environment Bilotti, Katharina; Kennedy, Erin E.; Li, Chuxuan DNA Repair, Vol. 59 https://doi.org/10.1016/j.dnarep.2017.08.010	journal	November 2017
APE1: A skilled nucleic acid surgeon Whitaker, Amy M.; Freudenthal, Bret D. DNA Repair, Vol. 71 https://doi.org/10.1016/j.dnarep.2018.08.012	journal	November 2018
Nucleosomes and the three glycosylases: High, medium, and low levels of excision by the uracil DNA glycosylase superfamily Tarantino, Mary E.; Dow, Blaine J.; Drohat, Alexander C. DNA Repair, Vol. 72 https://doi.org/10.1016/j.dnarep.2018.09.008	journal	December 2018
3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM Punjani, Ali; Fleet, David J. Journal of Structural Biology, Vol. 213, Issue 2 https://doi.org/10.1016/j.jsb.2021.107702	journal	June 2021
Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD Hewitt, Graeme; Borel, Valerie; Segura-Bayona, Sandra Molecular Cell, Vol. 81, Issue 4 https://doi.org/10.1016/j.molcel.2020.12.006	journal	February 2021
Impact of abasic site orientation within nucleosomes on human APE1 endonuclease activity Hinz, John M. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 766-767 https://doi.org/10.1016/j.mrfmmm.2014.05.008	journal	August 2014
Human Oxoguanine Glycosylase 1 Removes Solution Accessible 8-Oxo-7,8-dihydroguanine Lesions from Globally Substituted Nucleosomes Except in the Dyad Region Bilotti, Katharina; Tarantino, Mary E.; Delaney, Sarah Biochemistry, Vol. 57, Issue 9 https://doi.org/10.1021/acs.biochem.7b01125	journal	January 2018
Histone H3 Lysine 56 Acetylation Enhances AP Endonuclease 1-Mediated Repair of AP Sites in Nucleosome Core Particles Rodriguez, Yesenia; Horton, Julie K.; Wilson, Samuel H. Biochemistry, Vol. 58, Issue 35 https://doi.org/10.1021/acs.biochem.9b00433	journal	August 2019
Differential Ability of Five DNA Glycosylases to Recognize and Repair Damage on Nucleosomal DNA Olmon, Eric D.; Delaney, Sarah ACS Chemical Biology, Vol. 12, Issue 3 https://doi.org/10.1021/acschembio.6b00921	journal	January 2017
Global Repair Profile of Human Alkyladenine DNA Glycosylase on Nucleosomes Reveals DNA Packaging Effects Kennedy, Erin E.; Li, Chuxuan; Delaney, Sarah ACS Chemical Biology, Vol. 14, Issue 8 https://doi.org/10.1021/acschembio.9b00263	journal	July 2019
Enzymatic Excision of Uracil Residues in Nucleosomes Depends on the Local DNA Structure and Dynamics Ye, Yu; Stahley, Mary R.; Xu, Jianqing Biochemistry, Vol. 51, Issue 30 https://doi.org/10.1021/bi3006412	journal	July 2012
Nucleosome Core Particle-Catalyzed Strand Scission at Abasic Sites Sczepanski, Jonathan T.; Zhou, Chuanzheng; Greenberg, Marc M. Biochemistry, Vol. 52, Issue 12 https://doi.org/10.1021/bi3010076	journal	March 2013
Structure and Mechanism of DNA Polymerase β Beard, William A.; Wilson, Samuel H. Chemical Reviews, Vol. 106, Issue 2 https://doi.org/10.1021/cr0404904	journal	February 2006
Mechanistic Studies on Histone Catalyzed Cleavage of Apyrimidinic/Apurinic Sites in Nucleosome Core Particles Zhou, Chuanzheng; Sczepanski, Jonathan T.; Greenberg, Marc M. Journal of the American Chemical Society, Vol. 134, Issue 40 https://doi.org/10.1021/ja306858m	journal	September 2012
DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination Mol, Clifford D.; Izumi, Tadahide; Mitra, Sankar Nature, Vol. 403, Issue 6768 https://doi.org/10.1038/35000249	journal	January 2000
Instability and decay of the primary structure of DNA Lindahl, Tomas Nature, Vol. 362, Issue 6422 https://doi.org/10.1038/362709a0	journal	April 1993
Crystal structure of the nucleosome core particle at 2.8 Å resolution Luger, Karolin; Mäder, Armin W.; Richmond, Robin K. Nature, Vol. 389, Issue 6648 https://doi.org/10.1038/38444	journal	September 1997
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
Capturing snapshots of APE1 processing DNA damage Freudenthal, Bret D.; Beard, William A.; Cuneo, Matthew J. Nature Structural & Molecular Biology, Vol. 22, Issue 11 https://doi.org/10.1038/nsmb.3105	journal	October 2015
Nucleosomes facilitate their own invasion Li, Gu; Widom, Jonathan Nature Structural & Molecular Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nsmb801	journal	July 2004
Anomalous collapses of Nares Strait ice arches leads to enhanced export of Arctic sea ice Moore, G. W. K.; Howell, S. E. L.; Brady, M. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-020-20314-w	journal	January 2021
ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells Verma, Priyanka; Zhou, Yeqiao; Cao, Zhendong Nature Cell Biology, Vol. 23, Issue 2 https://doi.org/10.1038/s41556-020-00624-3	journal	January 2021
DNA damage detection in nucleosomes involves DNA register shifting Matsumoto, Syota; Cavadini, Simone; Bunker, Richard D. Nature, Vol. 571, Issue 7763 https://doi.org/10.1038/s41586-019-1259-3	journal	May 2019
Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function Dodonova, Svetlana O.; Zhu, Fangjie; Dienemann, Christian Nature, Vol. 580, Issue 7805 https://doi.org/10.1038/s41586-020-2195-y	journal	April 2020
Damage sensor role of UV-DDB during base excision repair Jang, Sunbok; Kumar, Namrata; Beckwitt, Emily C. Nature Structural & Molecular Biology, Vol. 26, Issue 8 https://doi.org/10.1038/s41594-019-0261-7	journal	July 2019
Rotational dynamics of DNA on the nucleosome surface markedly impact accessibility to a DNA repair enzyme Hinz, J. M.; Rodriguez, Y.; Smerdon, M. J. Proceedings of the National Academy of Sciences, Vol. 107, Issue 10 https://doi.org/10.1073/pnas.0914443107	journal	February 2010
Suppressed catalytic activity of base excision repair enzymes on rotationally positioned uracil in nucleosomes Beard, B. C.; Wilson, S. H.; Smerdon, M. J. Proceedings of the National Academy of Sciences, Vol. 100, Issue 13 https://doi.org/10.1073/pnas.1330328100	journal	June 2003
The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Xanthoudakis, S.; Smeyne, R. J.; Wallace, J. D. Proceedings of the National Academy of Sciences, Vol. 93, Issue 17 https://doi.org/10.1073/pnas.93.17.8919	journal	August 1996
Abasic Sites Stimulate Double-stranded DNA Cleavage Mediated by Topoisomerase II: DNA LESIONS AS ENDOGENOUS TOPOISOMERASE II POISONS Kingma, Paul S.; Corbett, Anita H.; Burcham, Philip C. Journal of Biological Chemistry, Vol. 270, Issue 37 https://doi.org/10.1074/jbc.270.37.21441	journal	September 1995
Uracil DNA Glycosylase Activity on Nucleosomal DNA Depends on Rotational Orientation of Targets Cole, Hope A.; Tabor-Godwin, Jenna M.; Hayes, Jeffrey J. Journal of Biological Chemistry, Vol. 285, Issue 4 https://doi.org/10.1074/jbc.M109.073544	journal	January 2010
Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyrimidinic Endonuclease APE1 and Endonuclease IV DNA Repair Enzymes Tsutakawa, Susan E.; Shin, David S.; Mol, Clifford D. Journal of Biological Chemistry, Vol. 288, Issue 12 https://doi.org/10.1074/jbc.M112.422774	journal	January 2013
The Structural Location of DNA Lesions in Nucleosome Core Particles Determines Accessibility by Base Excision Repair Enzymes Rodriguez, Yesenia; Smerdon, Michael J. Journal of Biological Chemistry, Vol. 288, Issue 19 https://doi.org/10.1074/jbc.M112.441444	journal	March 2013
Reduced Nuclease Activity of Apurinic/Apyrimidinic Endonuclease (APE1) Variants on Nucleosomes Hinz, John M.; Mao, Peng; McNeill, Daniel R. Journal of Biological Chemistry, Vol. 290, Issue 34 https://doi.org/10.1074/jbc.M115.665547	journal	August 2015
Site-specific Acetylation of Histone H3 Decreases Polymerase β Activity on Nucleosome Core Particles in Vitro Rodriguez, Yesenia; Hinz, John M.; Laughery, Marian F. Journal of Biological Chemistry, Vol. 291, Issue 21 https://doi.org/10.1074/jbc.M116.725788	journal	May 2016
The Human Ligase IIIα-XRCC1 Protein Complex Performs DNA Nick Repair after Transient Unwrapping of Nucleosomal DNA Cannan, Wendy J.; Rashid, Ishtiaque; Tomkinson, Alan E. Journal of Biological Chemistry, Vol. 292, Issue 13 https://doi.org/10.1074/jbc.M116.736728	journal	March 2017
Pre-steady-state Kinetic Characterization of the AP Endonuclease Activity of Human AP Endonuclease 1 Maher, Robyn L.; Bloom, Linda B. Journal of Biological Chemistry, Vol. 282, Issue 42 https://doi.org/10.1074/jbc.M704341200	journal	August 2007
DNA base excision repair of uracil residues in reconstituted nucleosome core particles Nilsen, H. The EMBO Journal, Vol. 21, Issue 21 https://doi.org/10.1093/emboj/cdf581	journal	November 2002
PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA Adasme, Melissa F.; Linnemann, Katja L.; Bolz, Sarah Naomi Nucleic Acids Research, Vol. 49, Issue W1 https://doi.org/10.1093/nar/gkab294	journal	May 2021
Unencumbered Pol β lyase activity in nucleosome core particles Rodriguez, Yesenia; Howard, Michael J.; Cuneo, Matthew J. Nucleic Acids Research, Vol. 45, Issue 15 https://doi.org/10.1093/nar/gkx593	journal	July 2017
Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity Mao, Peng; Brown, Alexander J.; Malc, Ewa P. Genome Research, Vol. 27, Issue 10 https://doi.org/10.1101/gr.225771.117	journal	September 2017
Distinct roles for RSC and SWI/SNF chromatin remodelers in genomic excision repair Bohm, Kaitlynne A.; Hodges, Amelia J.; Czaja, Wioletta Genome Research, Vol. 31, Issue 6 https://doi.org/10.1101/gr.274373.120	journal	May 2021
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Mechanisms of OCT4-SOX2 motif readout on nucleosomes Michael, Alicia K.; Grand, Ralph S.; Isbel, Luke Science, Vol. 368, Issue 6498 https://doi.org/10.1126/science.abb0074	journal	April 2020
ATP-Dependent Chromatin Remodeling Is Required for Base Excision Repair in Conventional but Not in Variant H2A.Bbd Nucleosomes Menoni, Hervé; Gasparutto, Didier; Hamiche, Ali Molecular and Cellular Biology, Vol. 27, Issue 17 https://doi.org/10.1128/MCB.00376-07	journal	September 2007
Initiation of Base Excision Repair of Oxidative Lesions in Nucleosomes by the Human, Bifunctional DNA Glycosylase NTH1 Prasad, Amalthiya; Wallace, Susan S.; Pederson, David S. Molecular and Cellular Biology, Vol. 27, Issue 24 https://doi.org/10.1128/MCB.00791-07	journal	December 2007
Nucleosome Disruption by DNA Ligase III-XRCC1 Promotes Efficient Base Excision Repair Odell, Ian D.; Barbour, Joy-El; Murphy, Drew L. Molecular and Cellular Biology, Vol. 31, Issue 22 https://doi.org/10.1128/MCB.05715-11	journal	November 2011
Mutagenesis by Apurinic/Apyrimidinic Sites Loeb, L. A.; Preston, B. D. Annual Review of Genetics, Vol. 20, Issue 1 https://doi.org/10.1146/annurev.ge.20.120186.001221	journal	December 1986
A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents McNeill, D. R.; Wilson, D. M. Molecular Cancer Research, Vol. 5, Issue 1 https://doi.org/10.1158/1541-7786.MCR-06-0329	journal	January 2007
Impairment of APE1 Function Enhances Cellular Sensitivity to Clinically Relevant Alkylators and Antimetabolites McNeill, Daniel R.; Lam, Wing; DeWeese, Theodore L. Molecular Cancer Research, Vol. 7, Issue 6 https://doi.org/10.1158/1541-7786.MCR-08-0519	journal	June 2009
FACT Assists Base Excision Repair by Boosting the Remodeling Activity of RSC Charles Richard, John Lalith; Shukla, Manu Shubhdarshan; Menoni, Hervé PLOS Genetics, Vol. 12, Issue 7 https://doi.org/10.1371/journal.pgen.1006221	journal	July 2016
ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair Tsuda, Masataka; Cho, Kosai; Ooka, Masato PLOS ONE, Vol. 12, Issue 11 https://doi.org/10.1371/journal.pone.0188320	journal	November 2017
PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling van Beek, Lotte; McClay, Éilís; Patel, Saleha International Journal of Molecular Sciences, Vol. 22, Issue 10 https://doi.org/10.3390/ijms22105112	journal	May 2021

Similar Records

Capturing snapshots of APE1 processing DNA damage

Journal Article · Sun Oct 11 20:00:00 EDT 2015 · Nature Structural & Molecular Biology · OSTI ID:1261477

DNA repair of a single UV photoproduct in a designed nucleosome

Journal Article · Tue Aug 28 00:00:00 EDT 2001 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:15003080

Regulation of oxidized base damage repair by chromatin assembly factor 1 subunit A

Journal Article · Wed Oct 26 20:00:00 EDT 2016 · Nucleic Acids Research · OSTI ID:1625548

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA
DNA repair enzymes
cryoelectron microscopy

Structural basis for $$\mathrm{APE1}$$ processing $$\mathrm{DNA}$$ damage in the nucleosome

Citation Formats

References (62)

Similar Records

Related Subjects