Article
Oncology
Emad Matanes, Vanessa M. Lopez-Ozuna, David Octeau, Tahira Baloch, Florentin Racovitan, Amandeep Kaur Dhillon, Roy Kessous, Oded Raban, Liron Kogan, Shannon Salvador, Susie Lau, Walter H. Gotlieb, Amber Yasmeen
Summary: The study showed that PARG inhibition can complement PARP inhibition in the treatment of ovarian cancer, especially in the presence of homologous recombination defects. PARG inhibitor alone or in combination with PARPi or Cisplatin can reduce cell migration and induce cell death.
FRONTIERS IN ONCOLOGY
(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)
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.
Review
Chemistry, Medicinal
Arwa AlGhamdi, Hanine AlMubayedh
Summary: This report reviews the usage, drug design and development of PARPi from the past to present, current issues, and future plans.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2022)
Article
Oncology
William P. Tew, Christina Lacchetti, Elise C. Kohn
Summary: ASCO Rapid Recommendations Updates provide revisions to select ASCO guideline recommendations based on new and practice-changing data. The goal is to disseminate updated recommendations in a timely manner to inform health practitioners and the public on the best available cancer care options.
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Review
Oncology
Andrisha-Jade Inderjeeth, Monique Topp, Elaine Sanij, Elena Castro, Shahneen Sandhu
Summary: This article summarizes the treatment advances in metastatic prostate cancer and the use of PARP inhibitors. Approximately a quarter of advanced prostate cancer patients have alterations in DNA repair pathways, making them eligible for treatment with PARP inhibitors. PARP inhibitors can be used as monotherapy and in combination with other drugs, providing additional treatment benefits.
Article
Biochemistry & Molecular Biology
David Hutin, Karoline Alvik Hagen, Peng Shao, Kim Sugamori, Denis M. Grant, Jason Matthews
Summary: PARP7 is an important regulator of the immune system, and is involved in intestinal inflammation. Loss of PARP7 impairs immune response to colon inflammation, possibly due to its role in IFN-I signaling rather than AHR signaling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Pablo Iglesias, Marcos Seoane, Irene Golan-Cancela, Maximo Fraga, Victor M. Arce, Jose A. Costoya
Summary: In recent years, new therapies targeting molecular mechanisms involved in the oncogenic process have been developed, including poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. PARP1 has shown therapeutic potential in certain tumor types, leading to the development of small molecule inhibitors. Many PARP inhibitors are currently being tested in clinical trials for the treatment of HR-deficient tumors and BRCA-related cancers. Additionally, PARP enzymes have been found to have cellular functions beyond DNA repair, such as post-translational modification of transcription factors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Medicine, Research & Experimental
Komal Thapa, Heena Khan, Uma Sharma, Amarjot Kaur Grewal, Thakur Gurjeet Singh
Summary: This review discussed the role of PARP-1 in neurodegenerative diseases and various FDA-approved PARP-1 inhibitors. Studies have shown that targeting PARP with chemical inhibitors may have therapeutic outcomes in neurodegenerative diseases.
Article
Oncology
Yaroslava Karpova, Danping Guo, Peter Makhov, Adam M. Haines, Dmitriy A. Markov, Vladimir Kolenko, Alexei V. Tulin
Summary: We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with the accumulation of poly(ADPribose) due to increased PARP-1 and decreased PARG levels. Modulation of gene expression is a primary cause for the observed anti-tumor effects, with PARP-1 and PARG enzymes playing a crucial role in regulating pADPr level. Interest in PARP-1 inhibitors has increased due to their recognized antitumor efficacy in disrupting malignancy in ccRCC cells.
Article
Pathology
Fabio Aimi, Holger Moch, Peter Schraml, Michael O. Hottiger
Summary: The study used a new anti-ADP-ribose antibody to assess ADPR levels in various cancer types, finding predominant cytoplasmic ADPR staining. Strong cytoplasmic ADPR levels were associated with better overall survival in specific breast and ovarian cancer types. Different cyADPR staining patterns correlated with early tumor stages and absence of lymph node metastasis, potentially influencing response rates to PARP inhibitors.
Article
Biochemistry & Molecular Biology
Julia M. Reber, Aswin Mangerich
Summary: Poly(ADP-ribosyl)ation, or PARylation, is a multifaceted post-translational modification with important roles in cellular processes and biomolecular condensate dynamics. Understanding the structural diversity of PAR and its interaction with other post-translational modifications, natural PARP variants, and accessory factors is crucial for the development of new therapeutic approaches. Targeting the enzymatic functions of PARPs, rather than complete inhibition, holds potential for innovative treatments in the future.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Palak Tiwari, Heena Khan, Thakur Gurjeet Singh, Amarjot Kaur Grewal
Summary: Stroke, a leading cause of morbidity and mortality, can be treated using various mechanistic approaches, including inhibition of poly (ADP-ribose) polymerase (PARP). PARP plays an important role in cerebral stroke, ischemia/reperfusion, and neurotrauma, and its inhibition has shown neuroprotective effects. However, the long-term side effects of PARP inhibitors need further investigation. Despite this, PARP inhibitors have shown promise in clinical trials for the treatment of various disorders.
NEUROCHEMICAL RESEARCH
(2022)
Review
Cell Biology
Jonathan Wooten, Nicole Mavingire, Katherine Damar, Andrea L. Perez, Eileen Brantley
Summary: Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair mechanisms, and PARP inhibitors (PARPi) show synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Triple-negative breast cancer (TNBC) patients with HR mediator mutations, such as BRCA1 and BRCA2, can respond to PARPi. However, PARPi resistance is a common issue. This review discusses the roles of PARP in DNA repair, mechanisms of PARPi resistance in TNBC, and recent advances in overcoming PARPi resistance in TNBC.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
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
Multidisciplinary Sciences
Tanay Thakar, Wendy Leung, Claudia M. Nicolae, Kristen E. Clements, Binghui Shen, Anja-Katrin Bielinsky, George-Lucian Moldovan
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Sanket Awate, Joshua A. Sommers, Arindam Datta, Sumeet Nayak, Marina A. Bellani, Olivia Yang, Christopher A. Dunn, Claudia M. Nicolae, George-Lucian Moldovan, Michael M. Seidman, Sharon B. Cantor, Robert M. Brosh
NUCLEIC ACIDS RESEARCH
(2020)
Article
Multidisciplinary Sciences
Kristen E. Clements, Emily M. Schleicher, Tanay Thakar, Anastasia Hale, Ashna Dhoonmoon, Nathanial J. Tolman, Anchal Sharma, Xinwen Liang, Yuka Imamura Kawasawa, Claudia M. Nicolae, Hong-Gang Wang, Subhajyoti De, George-Lucian Moldovan
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Tanay Thakar, George-Lucian Moldovan
Summary: Replication fork reversal is a universal response to replication stress, but reversed forks are susceptible to nucleolytic digestion and rely on specific mechanisms for protection. The BRCA pathway plays a crucial role in maintaining fork stability, and its deficiency leads to degradation of reversed forks, genome instability, and chemosensitivity.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Michael J. O'Connor, Tanay Thakar, Claudia M. Nicolae, George-Lucian Moldovan
Summary: PARP14 is identified as a regulator of cyclin D1 expression, with its depletion leading to decreased cyclin D1 protein levels and G1 cell-cycle arrest. This regulation is achieved through controlling cyclin D1 mRNA levels and is dependent on an intact p53-p21 pathway. The findings highlight a new role for PARP14 in promoting cell-cycle progression through cyclin D1 and the p53 pathway.
Article
Biochemistry & Molecular Biology
Lindsey M. Jackson, Ashna Dhoonmoon, Anastasia Hale, Kady A. Dennis, Emily M. Schleicher, Claudia M. Nicolae, George-Lucian Moldovan
Summary: Understanding the role of MED12 in regulating chemosensitivity in BRCA-deficient cells sheds light on a potential biomarker for predicting tumor response to therapy. Loss of MED12 confers resistance to cisplatin and PARP inhibitors, with its function in suppressing the TGF beta pathway playing a key role in chemoresistance. The MED12-TGF beta module is identified as a crucial regulator of genomic stability and chemosensitivity in BRCA-deficient cells.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Multidisciplinary Sciences
Arindam Datta, Kajal Biswas, Joshua A. Sommers, Haley Thompson, Sanket Awate, Claudia M. Nicolae, Tanay Thakar, George-Lucian Moldovan, Robert H. Shoemaker, Shyam K. Sharan, Robert M. Brosh
Summary: WRN helicase promotes stalled fork recovery and limits excessive degradation in BRCA2-deficient cancer cells, enhancing cell viability and potentiating PARP inhibitor cytotoxicity.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Emily M. Schleicher, Ashna Dhoonmoon, Lindsey M. Jackson, Jude B. Khatib, Claudia M. Nicolae, George-Lucian Moldovan
Summary: Maintenance of replication fork stability is crucial for genome preservation and is regulated by the ATM and ATR kinases. The TIP60-ATM pathway promotes replication fork reversal by recruiting SMARCAL1, enabling fork degradation in BRCA-deficient cells. CRISPR knockout screens identified genetic factors that affect cellular sensitivity to ATM inhibitors.
Article
Multidisciplinary Sciences
Ashna Dhoonmoon, Claudia M. Nicolae, George-Lucian Moldovan
Summary: Suppression of nascent DNA degradation is an essential role of the BRCA pathway in genome protection. PARP14 is a critical co-factor of MRE11 and mediates its engagement in BRCA-deficient cells, while the KU complex protects reversed forks against EXO1-catalyzed degradation.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Tanay Thakar, Ashna Dhoonmoon, Joshua Straka, Emily M. Schleicher, Claudia M. Nicolae, George-Lucian Moldovan
Summary: This study reveals that lagging strand ssDNA gaps interfere with nucleosome assembly and drive replication fork degradation in BRCA-deficient cells. Correcting PCNA unloading defects and activating a compensatory histone deposition pathway can restore fork stability in BRCA-deficient cells.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Ashna Dhoonmoon, Claudia M. Nicolae
Summary: ADP-ribosylation, a post-translational modification, plays important roles in DNA repair, transcriptional regulation, and cellular proliferation. It can be classified into mono-ADP-ribosylation (MARylation) and poly-ADP-ribosylation (PARylation). PARP enzymes, including PARP1 and PARP2, are well-studied members of the ADP-ribosyltransferases (ARTs) family and have been explored as therapeutic targets. However, other members such as PARP10 and PARP14 have gained attention recently for their roles in genomic stability and carcinogenesis. This review focuses on summarizing the current knowledge of MARylation in DNA repair and cancer, with a special emphasis on PARP10 and PARP14. Their roles in cancer progression, response to chemotherapeutics, and known inhibitors are highlighted.
Article
Genetics & Heredity
Emily M. Schleicher, Ashna Dhoonmoon, Lindsey M. Jackson, Kristen E. Clements, Coryn L. Stump, Claudia M. Nicolae, George-Lucian Moldovan