Article
Multidisciplinary Sciences
Ezeogo Obaji, Mirko M. Maksimainen, Albert Galera-Prat, Lari Lehtio
Summary: Human PARP2 is an ADP-ribosyltransferase that catalyzes poly-ADP-ribosylation of itself, other proteins, and DNA when activated by 5-phosphorylated DNA ends. The crystal structure of PARP2 bound to an activating DNA fragment reveals structural changes that lead to PARP2 activation and initiation of DNA repair processes. Comparison with PARP1 structures shows how binding to DNA damage sites induces a catalytically competent conformation in PARP2.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Dan Huang, W. Lee Kraus
Summary: ADP-ribosylation is a post-translational modification of proteins catalyzed by ADP-ribosyl transferase enzymes. PARP1, as a member of the nuclear PARPs family, plays important roles in DNA repair, chromatin regulation, and gene expression. Recent studies have expanded our understanding of the diverse functions of ADP-ribosylation in various biological processes.
Article
Multidisciplinary Sciences
Johannes Rudolph, Genevieve Roberts, Karolin Luger
Summary: PARP1 and PARP2 are key enzymes in the DNA damage response. HPF1 plays an essential role in modulating the PARylation of histones by forming a complex with both PARP1 and PARP2. Results show how HPF1 can affect the binding affinity of certain inhibitors to PARP1.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Nootan Pandey, Ben E. Black
Summary: PARP-1 is an abundant ADP-ribosyl transfer-ase that plays a key role in DNA damage response. Novel PARP inhibitors can now be designed to treat cell toxicity caused by PARP-1 trapping on DNA.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Article
Multidisciplinary Sciences
Julien Brustel, Tetsuya Muramoto, Kazuki Fumimoto, Jessica Ellins, Catherine J. Pears, Nicholas D. Lakin
Summary: This study reveals that serine ADP-ribosylation of histones maintains genome stability by coupling DNA repair with mitotic entry.
NATURE COMMUNICATIONS
(2022)
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)
Article
Multidisciplinary Sciences
Marie-France Langelier, Ramya Billur, Aleksandr Sverzhinsky, Ben E. Black, John M. Pascal
Summary: HPF1 dynamically regulates the ADP-ribosylation activity of PARP1/2 by accelerating the initiation rate on serine residues; HPF1 efficiently modulates the catalytic output of PARP1/2 to ensure it does not interfere with PAR chain elongation; The study provides evidence for the prevalence of serine-ADP-ribose modification in cells and its importance in an acute DNA damage response.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Yuanjiang Wang, Kun Li, Wenqing Xu, Shaohua Gou
Summary: In this study, a series of novel PARP-1 inhibitors were designed and synthesized. Compound 19b and 19c exhibited stronger inhibitory activity and higher selectivity, with 19c showing superior sensitivity towards SK-OV-3 cells compared to Olaparib.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Johannes Rudolph, Uma M. Muthurajan, Megan Palacio, Jyothi Mahadevan, Genevieve Roberts, Annette H. Erbse, Pamela N. Dyer, Karolin Luger
Summary: PARP1 is a key player in DNA damage response and a target for cancer treatment. The BRCT domain binds to DNA without activating the catalytic domain. The DNA-binding properties of the BRCT domain contribute to the monkey-bar mechanism for DNA transfer of PARP1.
Article
Pharmacology & Pharmacy
Tingting Du, Zhihui Zhang, Jie Zhou, Li Sheng, Haiping Yao, Ming Ji, Bailing Xu, Xiaoguang Chen
Summary: YHP-836, a novel PARP inhibitor, demonstrates excellent inhibitory activity for both PARP1 and PARP2 enzymes and allosterically regulates them via DNA trapping. It shows cytotoxicity and induces cell cycle arrest in BRCA-mutated tumor cell lines, as well as sensitizes tumor cells to chemotherapy agents.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biology
Sridevi Challa, Keun W. Ryu, Amy L. Whitaker, Jonathan C. Abshier, Cristel Camacho, W. Lee Kraus
Summary: In this study, PAR Trackers were developed and characterized as highly sensitive tools for detecting ADPR in various experimental and biological systems, providing greater temporal and spatial precision.
Article
Multidisciplinary Sciences
Kai Wang, Yizhou Wu, Lizhu Lai, Xin Wang, Shuya Sun
Summary: This study reveals the conformational changes in PAPR1 and the differences in key residue interactions induced by inhibitors through comparative molecular dynamics simulations and energy decomposition. It shows that inhibitors indirectly affect some residues in the CAT domain that interact with DNA and other domains. Additionally, the binding energy of CAT/ligand may not accurately measure the ligand activity compared to PARP1/DNA/ligand.
Article
Multidisciplinary Sciences
Yilun Sun, Jiji Chen, Shar-yin N. Huang, Yijun P. Su, Wenjie Wang, Keli Agama, Sourav Saha, Lisa M. Jenkins, John M. Pascal, Yves Pommier
Summary: The study provides insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG stabilizes PARylation of TOP1cc, which blocks proteasomal degradation. Additionally, the research suggests a potential regulatory role of PARylation for repairing a broad range of DPCs.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Christopher A. Koczor, Kate M. Saville, Joel F. Andrews, Jennifer Clark, Qingming Fang, Jianfeng Li, Rasha Q. Al-Rahahleh, Md Ibrahim, Steven McClellan, Mikhail V. Makarov, Marie E. Migaud, Robert W. Sobol
Summary: Assembly and disassembly of DNA repair protein complexes at DNA damage sites are crucial for maintaining genomic integrity. The study reveals interdependence between Polθ and XRCC1 in complex assembly, the importance of PAR for repair-complex assembly, and the modulation of BER complex assembly by changes in NAD+. These findings also highlight the coordinated yet independent roles of PARP1, PARP2, and SIRT6 in facilitating BER.
Review
Biochemistry & Molecular Biology
Palmiro Poltronieri, Masanao Miwa, Mitsuko Masutani
Summary: ADP-ribosylation plays a crucial role in post-translational modifications of proteins, involving functions such as DNA repair, transcription, and cell signaling. Enzymes involved in monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling also play important roles in cancers, with potential applications in non-oncological diseases. The field is still actively uncovering novel enzymes at a rapid pace.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
