Article
Biology
Tatyana A. Kurgina, Nina A. Moor, Mikhail M. Kutuzov, Konstantin N. Naumenko, Alexander A. Ukraintsev, Olga Lavrik
Summary: The histone PARylation factor 1 (HPF1) has been found to stimulate the autoPARylation of PARP1 and PARP2 as well as the heteroPARylation of histones in the complex with nucleosome. The stimulatory action is dependent on the concentrations of HPF1 and NAD(+), with PARP2 showing more efficiency than PARP1 in the reaction. The dual function of HPF1 in maintaining PARP activity is also discussed.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Medicinal
Jeffrey W. Johannes, Amber Balazs, Derek Barratt, Michal Bista, Matthew D. Chuba, Sabina Cosulich, Susan E. Critchlow, Sebastien L. Degorce, Paolo Di Fruscia, Scott D. Edmondson, Kevin Embrey, Stephen Fawell, Avipsa Ghosh, Sonja J. Gill, Anders Gunnarsson, Sudhir M. Hande, Tom D. Heightman, Paul Hemsley, Giuditta Illuzzi, Jordan Lane, Carrie Larner, Elisabetta Leo, Lina Liu, Andrew Madin, Scott Martin, Lisa McWilliams, Mark J. O'Connor, Jonathan P. Orme, Fiona Pachl, Martin J. Packer, Xiaohui Pei, Andrew Pike, Marianne Schimpl, Hongyao She, Anna D. Staniszewska, Verity Talbot, Elizabeth Underwood, Jeffrey G. Varnes, Lin Xue, Tieguang Yao, Ke Zhang, Andrew X. Zhang, Xiaolan Zheng
Summary: PARP inhibitors have obtained regulatory approval in oncology for tumors with homologous recombination repair deficiency, including those with BRCA mutations. However, some inhibitors have failed in combination with first-line chemotherapies due to overlapping hematological toxicities. Current PARP inhibitors lack selectivity for PARP1, which may contribute to toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Hanwen Zhang, Xiaohui Lin, Shan Zha
Summary: Poly(ADP-ribose) polymerase-1 (PARP1) and 2 (PARP2) are important enzymes in cells that play a role in DNA repair and are targeted by PARP inhibitors in cancer therapy. Recent quantitative live-cell imaging studies have provided insights into the distinct DNA substrate specificities and recruitment mechanisms of PARP1 and PARP2, which have implications for cancer therapy and the toxicities of PARP inhibitors.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Multidisciplinary Sciences
Jyothi Mahadevan, Asmita Jha, Johannes Rudolph, Samuel Bowerman, Domenic Narducci, Anders S. Hansen, Karolin Luger
Summary: PARP1 contributes to genome architecture and DNA damage repair through its dynamic association with chromatin. PARP1/2 recognize damaged DNA and recruit the DNA repair machinery. Single-molecule microscopy in live cells revealed two classes of freely diffusing PARP1/2 and two classes of bound PARP1/2. Majority of PARP1/2 diffuse freely in both undamaged and damaged nuclei, while a small fraction becomes transiently bound upon laser-induced DNA damage. Treatment with PARP1/2 inhibitors in the presence of DNA damage causes subtle changes in the dynamics of bound PARP1/2, suggesting potential for targeted therapy.
Article
Biochemistry & Molecular Biology
Rabeya Bilkis, Robert J. Lake, Karen L. Cooper, Alan Tomkinson, Hua-Ying Fan
Summary: Cockayne syndrome protein B (CSB) collaborates with PARP1 in repairing oxidized DNA. CSB is recruited to damaged DNA by PARP1 and PARP2, and regulates single-strand break repair (SSBR). CSB-mediated SSBR primarily occurs at actively transcribed DNA regions, suggesting different mechanisms for SSBR based on transcription status.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Xiaopeng Peng, Wanyi Pan, Feng Jiang, Weiming Chen, Zetao Qi, Weijie Peng, Jianjun Chen
Summary: This review provides an overview of recent progress in PARP1-based drug discovery, focusing on PARP1 inhibitor-based combination therapy and other PARP1-targeting strategies. Co-crystal structures and binding interactions between PARP1 inhibitors and their target proteins are summarized. The challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.
PHARMACOLOGICAL RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Lotte van Beek, Eilis McClay, Saleha Patel, Marianne Schimpl, Laura Spagnolo, Taiana Maia de Oliveira
Summary: PARP 1-3 are multi-domain enzymes known for catalyzing covalent modification of proteins, DNA, and themselves, with important functions in DNA damage response and nucleosome remodelling. Activation of PARP occurs through DNA binding, and modulation of their activity with PARP inhibitors has shown success in cancer therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Nicholas A. W. Bell, Justin E. Molloy
Summary: In this study, a new experimental method was developed to measure the mechanical stability and interaction kinetics of proteins across the two ends of a DNA double-strand break. It was found that PARP2 forms a stable mechanical link across blunt-end 5;- phosphorylated DSBs and restores torsional continuity. In contrast, PARP1 was not observed to form a bridging interaction across blunt or short overhang DSBs and competed away PARP2 bridge formation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Natalya Maluchenko, Darya Koshkina, Anna Korovina, Vasily Studitsky, Alexey Feofanov
Summary: The cytotoxicity of poly(ADP-ribose-)polymerase-1 (PARP1) inhibitors (PARPi) in antitumor therapy is correlated with their trapping efficiency in cell chromatin. The interactions of PARP1-nucleosome complexes with PARPi were studied, and it was found that the efficiency of PARP1 trapping on nucleosomes is affected by the chromatin structure.
Article
Multidisciplinary Sciences
M. M. Kutuzov, E. A. Belousova, T. A. Kurgina, A. A. Ukraintsev, I. A. Vasil'eva, S. N. Khodyreva, O. I. Lavrik
Summary: The study revealed that the presence of PARP1 leads to the suppression of BER enzymes' activities, while PARP2 predominantly influences the last stage of BER. PARylation attenuates the inhibitory effect of PARP1, but results in Pol beta inhibition and significant stimulation of LigIII alpha by PARP2 in a NAD(+)-dependent manner.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Caiyu Sun, Weiqiang Jing, Gaozhong Xiong, Dapeng Ma, Yueke Lin, Xiaoting Lv, Yunxue Zhao, Xiaomin Ma, Lihui Zhu, Xuecheng Shen, Min Yang, Zhenzhi Qin, Yeping Cheng, Haocheng Xuan, Tao Li, Lihui Han
Summary: This study identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy showed significant anti-tumor effects without causing obvious side effects. The findings suggest that targeting both PARP1 and Src may broaden the strategies for HCC treatment and benefit patients with high Src activation and resistance to PARP1 inhibitors alone.
Article
Genetics & Heredity
Dora Antal, Agnes Por, Ilona Kovacs, Katalin Dull, Szilard Poliska, Gyula Ujlaki, Mate agoston Demeny, Attila Gabor Szollosi, Borbala Kiss, Andrea Szegedi, Peter Bai, Magdolna Szanto
Summary: This study found that PARP2 mRNA expression is increased in human psoriatic lesions. Through experiments in mouse and human cell models, we found that inhibition of PARP2 expression can alleviate psoriasis-like dermatitis by suppressing inflammation in keratinocytes through inhibition of estrogen biosynthesis.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2023)
Article
Biochemistry & Molecular Biology
Elise Rouleau-Turcotte, Dragomir B. Krastev, Stephen J. Pettitt, Christopher J. Lord, John M. Pascal
Summary: PARP1 can rapidly detect DNA strand break damage and activate the production of poly(ADP-ribose) by signaling break detection to its catalytic domain. This study provides insights into the contributions of the regulatory helical domain (HD) to PARP1 allostery and the interaction with DNA damage, as well as the mechanisms of PARP1 catalytic activation and retention on DNA damage.
Article
Biochemistry & Molecular Biology
Sabrina Dallavalle, Salvatore Princiotto, Luce M. Mattio, Roberto Artali, Loana Musso, Anna Avino, Ramon Eritja, Claudio Pisano, Raimundo Gargallo, Stefania Mazzini
Summary: DNA repair inhibitors, particularly PARP1 inhibitors, have emerged as a new approach in cancer chemotherapy. Recent studies have shown that certain PARP1 inhibitors can form defined complexes with G-quadruplex structures within the PARP1 gene promoter, suggesting the potential development of better binders to inhibit the enzyme activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Xiaohui Lin, Wenxia Jiang, Johannes Rudolph, Brian J. Lee, Karolin Luger, Shan Zha
Summary: Dual-inhibitors of PARP1 and PARP2 show promise as anti-cancer drugs due to their ability to block enzymatic activity and extend the lifetime of DNA damage-induced PARP1 and PARP2 foci. This study reveals that PARP inhibitors trap PARP2 by physically stalling PARP2 on DNA via the WGR-DNA interaction, while suppressing the rapid exchange of PARP2 dependent on PARP1 and PAR.
NUCLEIC ACIDS RESEARCH
(2022)
