Article
Biochemistry & Molecular Biology
Emilia Komulainen, Jack Badman, Stephanie Rey, Stuart Rulten, Limei Ju, Kate Fennell, Ilona Kalasova, Kristyna Ilievova, Peter J. McKinnon, Hana Hanzlikova, Kevin Staras, Keith W. Caldecott
Summary: The study demonstrates that high activity of DNA strand break sensor protein Parp1 in mice with Xrcc1 deletion can result in lethal seizures, which can be prevented and lifespan extended by inhibiting or deleting Parp1. This highlights PARP inhibition as a potential therapeutic approach for hereditary neurological diseases.
Review
Oncology
Laetitia Collet, Julien Peron, Frederique Penault-Llorca, Pascal Pujol, Jonathan Lopez, Gilles Freyer, Benoit You
Summary: The efficacy of PARPi has been demonstrated in patients with HER2-negative metastatic breast cancer carrying a germline BRCA mutation. Patients with ER+/HER2-BRCA-mutated breast cancer have a higher risk of early disease progression and benefit from PARPi, especially when prescribed before chemotherapy. Recent studies also show the potential benefits of PARPi in early breast cancer and HRD breast cancer. Therefore, early genotyping strategies for identifying high-risk ER+/HER2- HRD breast cancer patients are of great importance.
Article
Oncology
Louise Ramos, Sarah Truong, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Michael M. Lizardo, Taras Shyp, Sonia H. Y. Kung, Alireza M. Rezakhanlou, Htoo Zarni Oo, Hans Adomat, Stephane Le Bihan, Colin Collins, Jeffrey Bacha, Dennis Brown, John Langlands, Wang Shen, Nada Lallous, Poul H. Sorensen, Mads Daugaard
Summary: This study reports a novel bifunctional PARP inhibitor (kt-3283) that has dual activity towards PARP1/2 and HDAC enzymes in Ewing sarcoma cells. Compared to commonly used PARP and HDAC inhibitors, kt-3283 exhibits enhanced cytotoxicity and inhibition effects.
CLINICAL CANCER RESEARCH
(2023)
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.
Review
Oncology
N. Y. L. Ngoi, D. S. P. Tan
Summary: The recognition of homologous recombination deficiency in high-grade serous ovarian cancer has led to the development of PARP inhibitors as an important therapy. However, controversies exist around defining and evaluating HRD, and the dynamic nature of tumoral HRD status poses challenges. It is critical to optimize HRD testing to maximize the potential benefits of PARP inhibitors for patients with HGSOC.
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)
Review
Biochemistry & Molecular Biology
Fan Zhang, Zihua Gong
Summary: This review highlights the critical role of 53BP1 in coordinating DSB repair pathways and promoting NHEJ-mediated DSB repair. It also discusses how 53BP1 enhances the sensitivity of BRCA1-deficient cancers to PARPi, offering a new avenue for improving cancer therapy strategies.
JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B
(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)
Review
Biochemistry & Molecular Biology
Dale A. Ramsden, Andre Nussenzweig
Summary: Translocations occur when end of one chromosome break is joined to a different chromosome break, potentially leading to disease and cancer. Understanding the mechanisms and cellular responses to chromosome breaks is crucial in preventing translocations. The location of breaks plays a significant role in translocation potential.
Article
Oncology
Mark D. Stewart, Diana Merino Vega, Rebecca C. Arend, Jonathan F. Baden, Olena Barbash, Nike Beaubier, Grace Collins, Tim French, Negar Ghahramani, Patsy Hinson, Petar Jelinic, Matthew J. Marton, Kimberly McGregor, Jerod Parsons, Lakshman Ramamurthy, Mark Sausen, Ethan S. Sokol, Albrecht Stenzinger, Hillary Stires, Kirsten M. Timms, Diana Turco, Iris Wang, J. Andrew Williams, Elaine Wong-Ho, Jeff Allen
Summary: Homologous recombination deficiency (HRD) is a tumor phenotype characterized by the inability of cells to repair DNA double-strand breaks effectively. Research has identified opportunities to improve the consistency in defining HRD and measuring homologous repair status parameters, benefiting the broader cancer community.
Article
Cell Biology
Marta Llorens-Agost, Michael Ensminger, Hang Phuong Le, Anugrah Gawai, Jie Liu, Andres Cruz-Garcia, Sarita Bhetawal, Richard D. Wood, Wolf-Dietrich Heyer, Markus Loebrich
Summary: BRCA2-deficient cells are vulnerable to inactivation of DNA repair pathways for DSBs, which can be exploited clinically. RAD52 and BRCA2 regulate the TMEJ process by blocking the POL theta function, ensuring proper repair of DSBs in mitosis.
NATURE CELL BIOLOGY
(2021)
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
Biochemistry & Molecular Biology
Annie A. Demin, Kouji Hirota, Masataka Tsuda, Marek Adamowicz, Richard Hailstone, Jan Brazina, William Gittens, Ilona Kalasova, Zhengping Shao, Shan Zha, Hiroyuki Sasanuma, Hana Hanzlikova, Shunichi Takeda, Keith W. Caldecott
Summary: PARPs and XRCC1 accelerate mammalian DNA base excision repair (BER), where XRCC1 prevents excessive PARP1 engagement during BER and traps PARP1 on BER intermediates. Excessive PARP1 engagement poses a threat to genome integrity, while XRCC1 acts as an anti-trapper preventing toxic PARP1 activity. Deletion of PARP1 rescues BER and resistance to base damage in XRCC1-deficient cells.
Article
Biochemistry & Molecular Biology
Sijie Liu, Yu Hua, Jingna Wang, Lingyan Li, Junjie Yuan, Bo Zhang, Ziyang Wang, Jianguo Ji, Daochun Kong
Summary: Protection of 30 overhangs in DNA double-strand breaks (DSBs) repair is achieved through the transient formation of RNA-DNA hybrids, with RNA polymerase III (RNAPIII) responsible for synthesizing the RNA strand. CtIP and MRN nuclease activity are required for initiating RNAPIII-mediated RNA synthesis at DSBs. Reduced RNAPIII levels suppress homologous recombination (HR) and lead to genetic loss > 30 bp at DSBs.
Review
Pharmacology & Pharmacy
Qin Xu, Zhengyu Li
Summary: PARPi has become a crucial maintenance therapy for ovarian cancer, especially in non-BRCA mutated population. However, the lack of unified HRD status detection methods poses a challenge and further research is needed.
FRONTIERS IN PHARMACOLOGY
(2021)