Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1

Eustermann, Sebastian; Wu, Wing-Fung; Langelier, Marie-France; Yang, Ji-Chun; Easton, Laura E.; Riccio, Amanda A.; Pascal, John M.; Neuhaus, David

doi:10.1016/j.molcel.2015.10.032

Title: Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1

Journal Article · Tue Dec 01 00:00:00 EST 2015 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2015.10.032· OSTI ID:1378282

Eustermann, Sebastian; Wu, Wing-Fung; Langelier, Marie-France; Yang, Ji-Chun; Easton, Laura E.; Riccio, Amanda A.; Pascal, John M.; Neuhaus, David

Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1’s function remained obscure; inherent dynamics of SSBs and PARP-1’s multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1’s signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformability of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodifcation in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Finally, our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.

View Journal Article

Cite

Export

Save

Research Organization:: Thomas Jefferson Univ., Philadelphia, PA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1378282

Alternate ID(s):: OSTI ID: 1344495

Journal Information:: Molecular Cell, Journal Name: Molecular Cell Vol. 60 Journal Issue: 5; ISSN 1097-2765

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 172 works

Citation information provided by
Web of Science

Cited By (34)

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes Wigle, Tim J.; Church, W. David; Majer, Christina R. SLAS DISCOVERY: Advancing Life Sciences R&D https://doi.org/10.1177/2472555219883623	journal	December 2019
Rev1 is a base excision repair enzyme with 5′-deoxyribose phosphate lyase activity Prasad, Rajendra; Poltoratsky, Vladimir; Hou, Esther W. Nucleic Acids Research, Vol. 44, Issue 22 https://doi.org/10.1093/nar/gkw869	journal	September 2016
Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential: Bcl-2 Protects TK6 Cells Against Hydroquinone-Induced Apoptosis Chen, Yuting; Chen, Shaoyun; Liang, Hairong Environmental and Molecular Mutagenesis, Vol. 59, Issue 1 https://doi.org/10.1002/em.22126	journal	August 2017
Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity: PARP1-DNA binding and PARPi's cytotoxicity Chen, Hua-Dong; Chen, Chuan-Huizi; Wang, Yu-Ting International Journal of Cancer, Vol. 145, Issue 3 https://doi.org/10.1002/ijc.32131	journal	January 2019
Targeting DNA repair in cancer: current state and novel approaches Klinakis, Apostolos; Karagiannis, Dimitris; Rampias, Theodoros Cellular and Molecular Life Sciences, Vol. 77, Issue 4 https://doi.org/10.1007/s00018-019-03299-8	journal	October 2019
PARP Inhibition in Cancer: An Update on Clinical Development Sachdev, Esha; Tabatabai, Roya; Roy, Varun Targeted Oncology, Vol. 14, Issue 6 https://doi.org/10.1007/s11523-019-00680-2	journal	October 2019
RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients Tessari, Anna; Parbhoo, Kareesma; Pawlikowski, Meghan Oncogene, Vol. 37, Issue 50 https://doi.org/10.1038/s41388-018-0424-8	journal	August 2018
NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains Langelier, Marie-France; Zandarashvili, Levani; Aguiar, Pedro M. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03234-8	journal	February 2018
Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance Pettitt, Stephen J.; Krastev, Dragomir B.; Brandsma, Inger Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03917-2	journal	May 2018
Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation O’Sullivan, Julia; Tedim Ferreira, Maria; Gagné, Jean-Philippe Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-08859-x	journal	March 2019
The beginning of the end for conventional RECIST — novel therapies require novel imaging approaches Gerwing, Mirjam; Herrmann, Ken; Helfen, Anne Nature Reviews Clinical Oncology, Vol. 16, Issue 7 https://doi.org/10.1038/s41571-019-0169-5	journal	February 2019
ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes Grimaldi, Giovanna; Corda, Daniela Biochemical Society Transactions, Vol. 47, Issue 1 https://doi.org/10.1042/bst20180416	journal	February 2019
PARPs in genome stability and signal transduction: implications for cancer therapy Palazzo, Luca; Ahel, Ivan Biochemical Society Transactions, Vol. 46, Issue 6 https://doi.org/10.1042/bst20180418	journal	November 2018
Caspase-7 uses RNA to enhance proteolysis of poly(ADP-ribose) polymerase 1 and other RNA-binding proteins Desroches, Alexandre; Denault, Jean-Bernard Proceedings of the National Academy of Sciences, Vol. 116, Issue 43 https://doi.org/10.1073/pnas.1909283116	journal	October 2019
Chronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research Rusin, Andrej; Seymour, Colin; Mothersill, Carmel International Journal of Radiation Biology, Vol. 94, Issue 3 https://doi.org/10.1080/09553002.2018.1422871	journal	January 2018
Mechanistic insight into the role of Poly(ADP-ribosyl)ation in DNA topology modulation and response to DNA damage Matkarimov, Bakhyt T.; Zharkov, Dmitry O.; Saparbaev, Murat K. Mutagenesis, Vol. 35, Issue 1 https://doi.org/10.1093/mutage/gez045	journal	November 2019
Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro Talhaoui, Ibtissam; Lebedeva, Natalia A.; Zarkovic, Gabriella Nucleic Acids Research https://doi.org/10.1093/nar/gkw675	journal	July 2016
Fluorescent sensors of PARP-1 structural dynamics and allosteric regulation in response to DNA damage Steffen, Jamin D.; McCauley, Michael M.; Pascal, John M. Nucleic Acids Research https://doi.org/10.1093/nar/gkw710	journal	August 2016
PARP1 changes from three-dimensional DNA damage searching to one-dimensional diffusion after auto-PARylation or in the presence of APE1 Liu, Lili; Kong, Muwen; Gassman, Natalie R. Nucleic Acids Research, Vol. 45, Issue 22 https://doi.org/10.1093/nar/gkx1047	journal	November 2017
Characterization of DNA ADP-ribosyltransferase activities of PARP2 and PARP3: new insights into DNA ADP-ribosylation Zarkovic, Gabriella; Belousova, Ekaterina A.; Talhaoui, Ibtissam Nucleic Acids Research, Vol. 46, Issue 5 https://doi.org/10.1093/nar/gkx1318	journal	January 2018
APE2 promotes DNA damage response pathway from a single-strand break Lin, Yunfeng; Bai, Liping; Cupello, Steven Nucleic Acids Research, Vol. 46, Issue 5 https://doi.org/10.1093/nar/gky020	journal	January 2018
APE1 senses DNA single-strand breaks for repair and signaling Lin, Yunfeng; Raj, Jude; Li, Jia Nucleic Acids Research, Vol. 48, Issue 4 https://doi.org/10.1093/nar/gkz1175	journal	December 2019
Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins Alemasova, Elizaveta E.; Lavrik, Olga I. Nucleic Acids Research, Vol. 47, Issue 8 https://doi.org/10.1093/nar/gkz120	journal	February 2019
PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Gupte, Rebecca; Liu, Ziying; Kraus, W. Lee Genes & Development, Vol. 31, Issue 2 https://doi.org/10.1101/gad.291518.116	journal	January 2017
The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival Jubin, T.; Kadam, A.; Jariwala, M. Cell Proliferation, Vol. 49, Issue 4 https://doi.org/10.1111/cpr.12268	journal	June 2016
Reversible mono-ADP-ribosylation of DNA breaks Munnur, Deeksha; Ahel, Ivan The FEBS Journal, Vol. 284, Issue 23 https://doi.org/10.1111/febs.14297	journal	November 2017
PARP inhibitors: Synthetic lethality in the clinic Lord, Christopher J.; Ashworth, Alan Science, Vol. 355, Issue 6330 https://doi.org/10.1126/science.aam7344	journal	March 2017
Structural basis for allosteric PARP-1 retention on DNA breaks Zandarashvili, Levani; Langelier, Marie-France; Velagapudi, Uday Kiran Science, Vol. 368, Issue 6486 https://doi.org/10.1126/science.aax6367	journal	April 2020
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity Brady, Pamlea N.; Goel, Anupam; Johnson, Margaret A. Microbiology and Molecular Biology Reviews, Vol. 83, Issue 1 https://doi.org/10.1128/mmbr.00038-18	journal	December 2018
Protein–Protein Interactions in DNA Base Excision Repair Moor, N. A.; Lavrik, O. I. Biochemistry (Moscow), Vol. 83, Issue 4 https://doi.org/10.1134/s0006297918040120	journal	April 2018
Prospects for combining immune checkpoint blockade with PARP inhibition Li, Anping; Yi, Ming; Qin, Shuang Journal of Hematology & Oncology, Vol. 12, Issue 1 https://doi.org/10.1186/s13045-019-0784-8	journal	September 2019
Unanchored tri‐NEDD8 inhibits PARP‐1 to protect from oxidative stress‐induced cell death Keuss, Matthew J.; Hjerpe, Roland; Hsia, Oliver The EMBO Journal, Vol. 38, Issue 6 https://doi.org/10.15252/embj.2018100024	journal	February 2019
ADP-ribosylation: from molecular mechanisms to human disease Hoch, Nicolas C.; Polo, Luis M. Genetics and Molecular Biology, Vol. 43, Issue 1 suppl 1 https://doi.org/10.1590/1678-4685-gmb-2019-0075	journal	January 2020
Poly(ADP-Ribose) Polymerases in Plants and Their Human Counterparts: Parallels and Peculiarities Rissel, Dagmar; Peiter, Edgar International Journal of Molecular Sciences, Vol. 20, Issue 7 https://doi.org/10.3390/ijms20071638	journal	April 2019

Similar Records

Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair

Journal Article · Wed Jan 15 00:00:00 EST 2014 · Toxicology and Applied Pharmacology · OSTI ID:1378282

Sun, Xi; Zhou, Xixi; Du, Libo; +3 more

Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue

Journal Article · Fri Sep 15 00:00:00 EDT 2017 · Toxicology and Applied Pharmacology · OSTI ID:1378282

Ding, Xiaofeng; Zhou, Xixi; Cooper, Karen L.; +2 more

Anticancer effect of AZD2461 PARP inhibitor against colon cancer cells carrying wt or dysfunctional p53

Journal Article · Mon Nov 15 00:00:00 EST 2021 · Experimental Cell Research · OSTI ID:1378282

Romeo, Maria Anele; Gilardini Montani, Maria Saveria; Benedetti, Rossella; +6 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1

Citation Formats

Cited By (34)

Similar Records

Related Subjects