Review
Genetics & Heredity
Felix Prado
Summary: The DNA damage tolerance (DDT) response aims to complete DNA replication timely and safely by facilitating the advance of replication forks through blocking lesions. Accumulation of single-strand DNA (ssDNA), lesion bypass, and ssDNA filling are key processes involving low-fidelity polymerases and Rad51/ssDNA nucleofilament. Rad51, BRCA2, and Rad52 play critical roles in homologous recombination (HR) and have been shown to perform various functions in DDT mechanisms without requiring the strand exchange activity of Rad51.
Article
Biochemistry & Molecular Biology
Munan Shi, Jiajia Hou, Weichu Liang, Qianwen Li, Shan Shao, Shusheng Ci, Chuanjun Shu, Xingqi Zhao, Shanmeizi Zhao, Miaoling Huang, Congye Wu, Zhigang Hu, Lingfeng He, Zhigang Guo, Feiyan Pan
Summary: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is identified as a regulator of HR repair through HDAC1-dependent regulation of RAD51 stability. SRC signaling activates GAPDH nuclear translocation, which binds with HDAC1 to prevent RAD51 degradation. These findings reveal the importance of GAPDH in HR repair.
Article
Biochemical Research Methods
Viola Previtali, Samuel H. Myers, Laura Poppi, Kieran Wynne, Irene Casamassima, Stefania Girotto, Giuseppina Di Stefano, Fulvia Farabegoli, Marinella Roberti, Giorgio Oliviero, Andrea Cavalli
Summary: BRCA2 and RAD51 are two proteins involved in homologous recombination and DNA double strand break repair. The study used a mass spectrometry proteomic approach to obtain a proteomic fingerprint after cellular treatment with the myr-BRC4 peptide, and identified three downregulated proteins (FANCI, FANCD2, and RPA3). The downregulation of these proteins could be used as an indicator for monitoring HR impairment.
JOURNAL OF PROTEOMICS
(2023)
Article
Biochemistry & Molecular Biology
Jakub Muraszko, Karol Kramarz, Bilge Argunhan, Kentaro Ito, Gabriela Baranowska, Yumiko Kurokawa, Yasuto Murayama, Hideo Tsubouchi, Sarah Lambert, Hiroshi Iwasaki, Dorota Dziadkowiec
Summary: Rrp1 plays a role in modulating Rad51 function by alleviating toxicity associated with excessive Rad51 levels through its ATPase domain. It interacts directly with Rad51, removes it from double-stranded DNA, and has E3 ubiquitin ligase activity with Rad51 as a substrate, suggesting a multi-tiered regulation of Rad51 by Rrp1.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Cell Biology
Stephanie Tye, George E. Ronson, Joanna R. Morris
Summary: The protection of stalled DNA replication forks requires the coordination of multiple recombination proteins and the utilization of nucleases in a different way than in homologous recombination. Despite similarities, the protection mechanism at stalled forks has unique features compared to the RAD51 loading step in homologous recombination.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
Article
Oncology
Guonan Zhang, Jie Zhang, Yi Zhu, Hong Liu, Yu Shi, Kun Mi, Meiying Li, Qi Zhao, Ziyi Huang, Jianming Huang
Summary: Somatic mutations in the BRCA2 BRC domain are associated with increased sensitivity to platinum-based therapy and improved survival outcomes in high-grade serous ovarian cancer.
EXPERIMENTAL CELL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Luke A. Greenhough, Chih-Chao Liang, Ondrej Belan, Simone Kunzelmann, Sarah Maslen, Monica C. Rodrigo-Brenni, Roopesh Anand, Mark Skehel, Simon J. Boulton, Stephen C. West
Summary: Homologous recombination is a vital process in life, involved in replication fork protection, DNA repair, and genetic exchange. Mutations in key recombination genes increase the risk of various cancers and Fanconi anemia. The RAD51 paralogues, including RAD51B, RAD51C, RAD51D, and XRCC2, play important roles in these processes, as demonstrated by their structure and function in the RAD51B-RAD51C-RAD51D-XRCC2 complex (BCDX2). BCDX2 stimulates RAD51 filament formation for recombinational DNA repair, crucial for tumor avoidance.
Article
Biochemistry & Molecular Biology
Mengfan Tang, Zhen Chen, Chao Wang, Xu Feng, Namsoo Lee, Min Huang, Huimin Zhang, Siting Li, Yun Xiong, Junjie Chen
Summary: ASF1 associates with RIF1 and regulates its functions in the DNA damage response, restoring homologous recombination in BRCA1-deficient cells and decreasing telomere fusion in TRF2-depleted cells.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Aviv Meir, J. Brooks Crickard, Youngho Kwon, Patrick Sung, Eric C. Greene
Summary: Srs2 is a crucial DNA repair enzyme that regulates the formation of homologous recombination intermediates by removing a recombinase called Rad51. Recent research indicates that two motor proteins, Rad54 and Rdh54, can restrict the activity of Srs2 and facilitate the progression of recombination.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Wan-Chen Li, Chia-Yi Lee, Wei-Hsuan Lan, Tai-Ting Woo, Hou-Cheng Liu, Hsin-Yi Yeh, Hao-Yen Chang, Yu-Chien Chuang, Chiung-Ya Chen, Chi-Ning Chuang, Chia-Ling Chen, Yi-Ping Hsueh, Hung-Wen Li, Peter Chi, Ting-Fang Wang
Summary: Most eukaryotes possess two RecA-like recombinases for interhomolog recombination during meiosis, but some have lost Dmc1. TrRad51 in Trichoderma reesei plays a crucial role in interhomolog recombination and has better mismatch tolerance than ScRad51, evolving ScDmc1-like properties through structural variations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Lise M. van Wijk, Claire J. H. Kramer, Sylvia Vermeulen, Natalja T. ter Haar, Marthe M. de Jonge, Judith R. Kroep, Cor D. de Kroon, Katja N. Gaarenstroom, Harry Vrieling, Tjalling Bosse, Maaike P. G. Vreeswijk
Summary: This study improved and calibrated a RAD51-based functional HRD test to determine optimal test parameters, demonstrating the high sensitivity and specificity of the RAD51-FFPE test. It showed promising results in detecting BRCA deficient tumors and RECAP-HRD tumors, indicating its potential as an attractive alternative to DNA-based tests for routine diagnostic pathology.
Article
Genetics & Heredity
Jeanette H. Sutherland, William K. Holloman
Summary: BRC is a conserved sequence motif in BRCA2 tumor suppressor protein family, which interacts with RAD51 in DNA repair. It consists of two tetrameric sequence modules with hydrophobic residues separated by an intervening spacer region. Brh2 in Ustilago maydis is the only fungal BRCA2 ortholog with a single BRC, while others contain multiple tandem repeats. Comparative sequence analysis identified BRCA2 orthologs in other fungal phyla. A biological assay system was developed to evaluate BRC functionality and the importance of conserved amino acid residues in DNA repair. Certain BRC mutant variants, called antimorphs, were found to cause more severe DNA repair phenotypes than the null.
Article
Biochemistry & Molecular Biology
Yuqin Zhao, Kaiping Hou, Youhang Li, Shuailin Hao, Yu Liu, Yinan Na, Chao Li, Jian Cui, Xingzhi Xu, Xiaohua Wu, Hailong Wang
Summary: HELQ has opposing activities in regulating DNA end resection at double strand breaks (DSBs) and stalled forks, and plays a crucial role in maintaining genome stability.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Genetics & Heredity
Upasana Roy, Eric C. Greene
Summary: Homologous recombination (HR) is a crucial mechanism for the accurate repair of DNA double-stranded breaks and maintenance of genome integrity, with Rad51 recombinase playing a key role in eukaryotes. Rad51 paralogs, such as Rad55-Rad57 complex in yeast, regulate proper levels of HR and mutations in these genes are associated with diseases. Studies on Rad55-Rad57 in yeast have provided important insights into the conserved role of Rad51 paralogs in higher eukaryotes.
Review
Oncology
Claudia Piombino, Laura Cortesi
Summary: The role of the PARP1 enzyme in recognizing and signaling DNA damage is important. PARP inhibitors are primarily used to treat breast, ovarian, pancreatic, and prostate cancers with BRCA1 or BRCA2 pathogenic variants, but their widespread use has raised the issue of therapy resistance. This review summarizes key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors.
Article
Chemistry, Medicinal
Andrew J. Whitehouse, M. Daben J. Libardo, Monica Kasbekar, Paul D. Brear, Gerhard Fischer, Craig J. Thomas, Clifton E. Barry, Helena I. M. Boshoff, Anthony G. Coyne, Chris Abell
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Ana Trapero, Angela Pacitto, Daniel Shiu-Hin Chan, Chris Abell, Tom L. Blundell, David B. Ascher, Anthony G. Coyne
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Mohamad Sabbah, Vitor Mendes, Robert G. Vistal, David M. G. Dias, Monika Zahorszka, Katarina Mikusova, Jana Kordulakova, Anthony G. Coyne, Tom L. Blundell, Chris Abell
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Correction
Chemistry, Medicinal
Mohamad Sabbah, Vitor Mendes, Robert G. Vistal, David M. G. Dias, Monika Zahorszka, Katarina Mikusova, Jana Kordulakova, Anthony G. Coyne, Tom L. Blundell, Chris Abell
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Sherine E. Thomas, Andrew J. Whitehouse, Karen Brown, Sophie Burbaud, Juan M. Belardinelli, Jasper Sangen, Ramanuj Lahiri, Mark Daben J. Libardo, Pooja Gupta, Sony Malhotra, Helena I. M. Boshoff, Mary Jackson, Chris Abell, Anthony G. Coyne, Tom L. Blundell, Rodrigo Andres Floto, Vitor Mendes
NUCLEIC ACIDS RESEARCH
(2020)
Article
Chemistry, Medicinal
Duncan E. Scott, Timothy P. C. Rooney, Elliott D. Bayle, Tashfina Mirza, Henriette M. G. Willems, Jonathan H. Clarke, Stephen P. Andrews, John Skidmore
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Joao A. Ribeiro, Alexander Hammer, Gerardo A. Libreros-Zuniga, Sair M. Chavez-Pacheco, Petros Tyrakis, Gabriel S. de Oliveira, Timothy Kirkman, Jamal El Bakali, Silvana A. Rocco, Mauricio L. Sforca, Roberto Parise-Filho, Anthony G. Coyne, Tom L. Blundell, Chris Abell, Marcio V. B. Dias
ACS INFECTIOUS DISEASES
(2020)
Article
Multidisciplinary Sciences
Vitor Mendes, Simon R. Green, Joanna C. Evans, Jeannine Hess, Michal Blaszczyk, Christina Spry, Owain Bryant, James Cory-Wright, Daniel S-H Chan, Pedro H. M. Torres, Zhe Wang, Navid Nahiyaan, Sandra O'Neill, Sebastian Damerow, John Post, Tracy Bayliss, Sasha L. Lynch, Anthony G. Coyne, Peter C. Ray, Chris Abell, Kyu Y. Rhee, Helena I. M. Boshoff, Clifton E. Barry, Valerie Mizrahi, Paul G. Wyatt, Tom L. Blundell
Summary: Coenzyme A (CoA) is a crucial factor in various metabolic pathways and cellular processes, particularly in prokaryotes such as Mycobacterium tuberculosis. The biosynthesis of CoA involves five steps, with the second and third steps catalyzed by a bifunctional protein CoaBC in most prokaryotes. The researchers identified inhibitors of M. tuberculosis CoaB through a high-throughput screen and discovered a cryptic allosteric binding site within the enzyme.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Joanna C. Evans, Dinakaran Murugesan, John M. Post, Vitor Mendes, Zhe Wang, Navid Nahiyaan, Sasha L. Lynch, Stephen Thompson, Simon R. Green, Peter C. Ray, Jeannine Hess, Christina Spry, Anthony G. Coyne, Chris Abell, Helena I. M. Boshoff, Paul G. Wyatt, Kyu Y. Rhee, Tom L. Blundell, Clifton E. I. I. I. I. I. I. Barry, Valerie Mizrahi
Summary: Coenzyme A (CoA) is an essential cofactor in all living cells, and the pathway to CoA biosynthesis is considered a potential source of novel tuberculosis drug targets. This study identified a small molecule inhibitor, compound 1f, that displays on-target activity against Mtb CoaBC, confirming the druggability of this target. Metabolomic profiling following exposure to compound 1f in wild-type Mtb H37Rv produced a signature consistent with perturbations in pantothenate and CoA biosynthesis.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Helen K. Boffey, Timothy P. C. Rooney, Henriette M. G. Willems, Simon Edwards, Christopher Green, Tina Howard, Derek Ogg, Tamara Romero, Duncan E. Scott, David Winpenny, James Duce, John Skidmore, Jonathan H. Clarke, Stephen P. Andrews
Summary: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are promising therapeutic targets in diseases such as cancer, immunological disorders, and neurodegeneration. In this study, the physicochemical properties of a selective PI5P4K gamma inhibitor were improved, enabling its interaction with PI5P4K gamma in intact cells without inhibiting PI5P4K alpha or PI5P4K beta. The X-ray structure of PI5P4K gamma bound to an inhibitor revealed an allosteric binding mode.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biophysics
Tina Leontidou, Ziyi Yu, Jeannine Hess, Katrin Geisler, Alison G. Smith, Anthony Coyne, Chris Abell
Summary: We demonstrate the generation of novel composite hydrogel microparticles loaded with BODIPY 505/515, which can be used to deliver the dye to microalgal cells to stain the intracellular lipids. The microparticles were prepared by combining polymeric micelles with hydrogel technology to obtain microparticles of enhanced loading capacity. The method can also be used to stain other types of microalgal cells.
COLLOIDS AND SURFACES B-BIOINTERFACES
(2023)
Article
Chemistry, Multidisciplinary
Jamal El Bakali, Michal Blaszczyk, Joanna C. Evans, Jennifer A. Boland, William J. McCarthy, Imam Fathoni, Marcio V. B. Dias, Eachan O. Johnson, Anthony G. Coyne, Valerie Mizrahi, Tom L. Blundell, Chris Abell, Christina Spry
Summary: By performing a fragment screen, we identified three series of fragments that occupy distinct regions in the active site of MtbPPAT. Guided by X-ray crystal structures, we successfully linked weakly-binding fragments to produce an active site binder with Mtb activity, as demonstrated by CRISPR interference. This study represents a significant progress in validating MtbPPAT as a potential drug target and designing anti-TB drugs targeting MtbPPAT.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Biochemistry & Molecular Biology
William Addison, Martyn Frederickson, Anthony G. Coyne, Chris Abell
Summary: This article focuses on recent research on potential therapeutic targets for Mab infections and discusses various approaches used to discover small molecule inhibitors.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Duncan E. Scott, Nicola J. Francis-Newton, May E. Marsh, Anthony G. Coyne, Gerhard Fischer, Tommaso Moschetti, Andrew R. Bayly, Timothy D. Sharpe, Kalina T. Haas, Lorraine Barber, Chiara R. Valenzano, Rajavel Srinivasan, David J. Huggins, Miyoung Lee, Amy Emery, Bryn Hardwick, Matthias Ehebauer, Claudio Dagostin, Alessandro Esposito, Luca Pellegrini, Trevor Perrior, Grahame McKenzie, Tom L. Blundell, Marko Hyvonen, John Skidmore, Ashok R. Venkitaraman, Chris Abell
Summary: The study identifies CAM833 as an orthosteric inhibitor of RAD51:BRC, which affects DNA repair and potentiates cell death induced by DNA damage, working in coordination with PARP1 inhibitors to suppress growth in BRCA2-wildtype cells.
CELL CHEMICAL BIOLOGY
(2021)