Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells

Yang, Qianye; Liu, Yu; Sun, Rong; Li, Jian

doi:10.3389/fphar.2021.637825

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…An inhibitor of TRDMT1, an RNA methyltransferase involved in the transcription-coupled HR, sensitizes cancer cells to PARPi and ATRi ( Zhu et al 2021 ). Furthermore, a RAD52 inhibitor induces synthetic lethality in BRCA2-deficient cells ( Yang et al 2021 ), which is likely attributed to the indispensable HR function of RAD52 in the absence of BRCA2 ( Feng et al 2011 ). The deubiquitinase USP1 is required for the deubiquitination of PCNA and FANCD2, which are involved in TLS, template switching (TS), FA, and HR pathways ( Huang et al 2006 ; Oestergaard et al 2007 ).…”

Section: Targeting the Ddr In Cancer Therapymentioning

confidence: 99%

DNA repair defects in cancer and therapeutic opportunities

2022

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DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.

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Section: Targeting the Ddr In Cancer Therapymentioning

confidence: 99%

DNA repair defects in cancer and therapeutic opportunities

2022

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“…Chemotherapies targeting this specific pathway would then likely be more efficient. An example would be inhibition of RAD52, for which a leading compound has been identified [ 139 ]. On the other hand, reduced expression of CSB would predict a favorable response of tumor cells to chemotherapy.…”

Section: Csb and Its Implications In Targeted Therapy In Cancermentioning

confidence: 99%

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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“…Most campaigns to discover RAD52 inhibitors use virtual screening, docking the molecules in “druggable” RAD52 pockets that are considered important for their activity. Additionally, high-throughput screening (HTS) assays on RAD52 based on biochemical or biophysical assays (such as fluorescence polarization (FP) [ 65 ] and electrophoretic mobility shift assay (EMSA) [ 65 , 84 , 104 , 105 ]) are also widely used. Most of these assays measure compound binding by using a fluorescently labeled probe (e.g., cyanine5-labeled 30 nucleotides of ssDNA) to detect the inhibition of the DNA-RAD52 interaction via changes in electrophoretic mobility or donor-acceptor energy transfer.…”

Section: Rad52 Inhibition In Synthetic Lethality Therapiesmentioning

confidence: 99%

Novel Insights into RAD52’s Structure, Function, and Druggability for Synthetic Lethality and Innovative Anticancer Therapies

Balboni

Rinaldi

Previtali

et al. 2023

Cancers

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In recent years, the RAD52 protein has been highlighted as a mediator of many DNA repair mechanisms. While RAD52 was initially considered to be a non-essential auxiliary factor, its inhibition has more recently been demonstrated to be synthetically lethal in cancer cells bearing mutations and inactivation of specific intracellular pathways, such as homologous recombination. RAD52 is now recognized as a novel and critical pharmacological target. In this review, we comprehensively describe the available structural and functional information on RAD52. The review highlights the pathways in which RAD52 is involved and the approaches to RAD52 inhibition. We discuss the multifaceted role of this protein, which has a complex, dynamic, and functional 3D superstructural arrangement. This complexity reinforces the need to further investigate and characterize RAD52 to solve a challenging mechanistic puzzle and pave the way for a robust drug discovery campaign.

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Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells

Cited by 8 publications

References 33 publications

DNA repair defects in cancer and therapeutic opportunities

DNA repair defects in cancer and therapeutic opportunities

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Novel Insights into RAD52’s Structure, Function, and Druggability for Synthetic Lethality and Innovative Anticancer Therapies

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