RAD52: Paradigm of Synthetic Lethality and New Developments

Rossi, Matthew J.; DiDomenico, Sarah F.; Patel, Mikir; Mazin, Alexander V.

doi:10.3389/fgene.2021.780293

Cited by 38 publications

(46 citation statements)

References 156 publications

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“…RAD52 binds to ssDNA, promotes DNA annealing in the SSA pathway while it interacts with RAD51 to modulate its DNA strand-exchange activity in the HDR pathway. In addition, RAD52 protects stalled replication forks from degradation ( 177 – 180 ). RAD52-mediated annealing of large regions of a homologous sequence, independent of RAD51-mediated strand invasion is key for the SSA ( 181 ).…”

Section: Inhibitors Targeting Ssa and Alt-nhej (Tmej) Pathwaysmentioning

confidence: 99%

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

et al. 2022

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The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.

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Section: Inhibitors Targeting Ssa and Alt-nhej (Tmej) Pathwaysmentioning

confidence: 99%

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

et al. 2022

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“…RPA is subsequently replaced by RAD51 mediated by BRCA2, which itself is recruited to the DSB by BRCA1 and partner and localizer of BRCA2 (PALB2). The resulting RAD51-DNA nucleoprotein subsequently initiates homology search followed by displacement loop (D-loop) formation and strand invasion, a process in which RAD52 is involved [ 18 ]. DNA synthesis starts and can be mediated via distinct HR subpathways.…”

Section: The Homologous Recombination Repair Pathwaymentioning

confidence: 99%

Homologous Recombination Deficiency Scar: Mutations and Beyond—Implications for Precision Oncology

Wiel

Schuitmaker

Cong

et al. 2022

Cancers

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Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline BRCA1/2 mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss. HRD, regardless of BRCA1/2 status, is associated with specific forms of genomic and mutational signatures termed HRD scar. Detection of this HRD scar might therefore be a more reliable biomarker for HRD. This review discusses and compares different methods of assessing HRD and HRD scar, their advances into the clinic, and their potential implications for precision oncology.

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“…In canonical pathways, HR (or simply homologous recombination—HR) can only occur in the G2 and late S phases when a sister chromatid is available, whereas non-homologous end joining—NHEJ (also referred as canonical or classical NHEJ—cNHEJ, or DNA-PK-depended NHEJ—D-NHEJ) is used to repair DSBs during the G1 and early S cell cycle phases [ 17 ]. It is estimated that more than 90% of DNA double-strand breaks in mammals are repaired by NHEJ, while most of the damage in yeast and bacteria is repaired by HR [ 18 ]. A DNA double-strand break (DSB) repair (DSBR) pathway that employs homologous repeats flanking a DSB is known as single-strand annealing (SSA).…”

Section: The Role Of Polθ In Normal Cellsmentioning

confidence: 99%

Synthetic Lethality Targeting Polθ

Drzewiecka

Barszczewska-Pietraszek

Czarny

et al. 2022

Genes

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Research studies regarding synthetic lethality (SL) in human cells are primarily motivated by the potential of this phenomenon to be an effective, but at the same time, safe to the patient’s anti-cancer chemotherapy. Among the factors that are targets for the induction of the synthetic lethality effect, those involved in DNA repair seem to be the most relevant. Specifically, when mutation in one of the canonical DNA double-strand break (DSB) repair pathways occurs, which is a frequent event in cancer cells, the alternative pathways may be a promising target for the elimination of abnormal cells. Currently, inhibiting RAD52 and/or PARP1 in the tumor cells that are deficient in the canonical repair pathways has been the potential target for inducing the effect of synthetic lethality. Unfortunately, the development of resistance to commonly used PARP1 inhibitors (PARPi) represents the greatest obstacle to working out a successful treatment protocol. DNA polymerase theta (Polθ), encoded by the POLQ gene, plays a key role in an alternative DSB repair pathway—theta-mediated end joining (TMEJ). Thus, it is a promising target in the treatment of tumors harboring deficiencies in homologous recombination repair (HRR), where its inhibition can induce SL. In this review, the authors discuss the current state of knowledge on Polθ as a potential target for synthetic lethality-based anticancer therapies.

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RAD52: Paradigm of Synthetic Lethality and New Developments

Cited by 38 publications

References 156 publications

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

Homologous Recombination Deficiency Scar: Mutations and Beyond—Implications for Precision Oncology

Synthetic Lethality Targeting Polθ

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