FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(17), P. 9144 - 9165

Published: Aug. 1, 2023

FANCD2 protein, a key coordinator and effector of the interstrand crosslink repair pathway, is also required to prevent excessive nascent strand degradation at hydroxyurea-induced stalled forks. The RAD51 recombinase has been implicated in regulation resection replication mechanistic contributions these proteins fork protection are not well understood. Here, we used purified study how each protein regulates DNA We characterized three mechanisms FANCD2-mediated protection: (1) N-terminal domain inhibits essential DNA2 nuclease activity by directly binding accounting for over-resection defective cells. (2) Independent dimerization with FANCI, itself stabilizes filaments inhibit multiple nucleases, including DNA2, MRE11 EXO1. (3) Unexpectedly, uncovered new function: stabilizing filaments, acts stimulate exchange RAD51. Our work biochemically explains non-canonical which protect propose model provides simple molecular explanation genetic interactions between BRCA2 FA/BRCA pathway.

Language: Английский

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Crosstalk between Wnt/β-catenin signaling pathway and DNA damage response in cancer: a new direction for overcoming therapy resistance

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 2, 2023

Wnt signaling plays an important role in regulating the biological behavior of cancers, and many drugs targeting this have been developed. Recently, a series research revealed that could regulate DNA damage response (DDR) which is crucial for maintaining genomic integrity cells closely related to cancer genome instability. Many developed target cancers. Notably, different components DDR pathways are involved crosstalk, forming complex regulatory network providing new opportunities therapy. Here, we provide brief overview field review interactions between these two pathways. Finally, also discuss possibility therapeutic agents as potential treatment strategies.

Language: Английский

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For Better or Worse: Modulation of the Host DNA Damage Response by Human Papillomavirus

Annual Review of Virology, Journal Year: 2023, Volume and Issue: 10(1), P. 325 - 345

Published: April 11, 2023

High-risk human papillomaviruses (HPVs) are associated with several cancers. HPVs small, DNA viruses that rely on host cell machinery for viral replication. The HPV life cycle takes place in the stratified epithelium, which is composed of different states, including terminally differentiating cells no longer active cycle. have evolved mechanisms to persist and replicate epithelium by hijacking modulating cellular pathways, damage response (DDR). activate exploit DDR pathways promote replication, turn increases susceptibility genomic instability carcinogenesis. Here, we review recent advances our understanding regulation high-risk during discuss potential consequences pathways.

Language: Английский

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For better or worse: crosstalk of parvovirus and host DNA damage response

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 23, 2024

Parvoviruses are a group of non-enveloped DNA viruses that have broad spectrum natural infections, making them important in public health. NS1 is the largest and most complex non-structural protein parvovirus genome, which indispensable life cycle closely related to viral replication, induction host cell apoptosis, arrest, damage response (DDR), other processes. Parvovirus activates utilizes DDR pathway promote replication through NS1, thereby increasing pathogenicity cells. Here, we review latest progress regulating during lifecycle discuss potential cellular consequences pathway, targeting provide theoretical basis for further elucidation pathogenesis development new antiviral drugs.

Language: Английский

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DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Summary DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights involvement in metabolic and cardiovascular diseases. Elevated levels modified, damaged, or ectopically localized self‐DNA non‐self‐DNA have been observed patients animal models with obesity, diabetes, fatty liver disease, disease. The accumulation cytosolic aberrantly activates signaling pathways, driving pathological progression these disorders. This review roles specific sensors, such as cyclic AMP‐GMP synthase stimulator interferon genes (cGAS‐STING), absent melanoma 2 (AIM2), toll‐like receptor 9 (TLR9), gamma‐inducible protein 16 (IFI16), DNA‐dependent kinase (DNA‐PK), DEAD‐box helicase 41 (DDX41) various We explore how pathways both non‐immune cells contribute to development Furthermore, we discuss intricate interplay between stress responses, offering insights into potential therapeutic targets managing Understanding mechanisms sensor contexts provides a foundation developing novel interventions aimed at mitigating impact pervasive health issues.

Language: Английский

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

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: April 6, 2022

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

Language: Английский

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The immunotoxicity of natural and depleted uranium: From cells to people

Toxicology and Applied Pharmacology, Journal Year: 2022, Volume and Issue: 454, P. 116252 - 116252

Published: Sept. 21, 2022

Language: Английский

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Immunogenic chemotherapy: great potential for improving response rates

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Dec. 6, 2023

The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate by inducing immunogenic cell death and durably eradicate tumors. This suggests holds great potential for improving response rates. However, practice has only had limited success long-term survival or cure cancers when used either alone combination with immunotherapy. We think this because the importance dose, schedule, tumor model dependence chemotherapy-activated under-appreciated. Here, we review immune modulation function representative propose a chemotherapy-induced long-lasting responses rely on synergetic interaction between killing cells immunity. comb through treatment schedules, identify needs dose schedule optimization therapy immunotherapy dosage responsiveness too low. further intrinsic factors affect optimal schedule. Lastly, biomarkers indicating to and/or treatments. A deep understanding how activates monitor its lead development more effective chemo-immunotherapy, thereby efficacy cancer treatment.

Language: Английский

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Insight into the anti-cancer and anti-viral therapeutic properties of biological active molecule prodigiosin

Asia-Pacific Journal of Pharmacotherapy & Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Bioactive compounds from natural sources play an important role as immunomodulator in diseases such cancer, inflammatory and viral diseases. Immunomodulator functions to regulate the immune system defends against infectious foreign particles. Naturally occurring bioactive have been shown boost immunity increase anti-cancer response, well cancer patients. Prodigiosin is reported anticancer agent effective multiple tumor cell lines also combat Innate cytotoxicity one of main problems linked with use immunosuppressants, especially oncology that leads scientists toward application combined regimens. In this perception, prodigiosin offers interesting perspective combinatorial applications. However, major devastating limitation associated its strain: Serratia marcescens source a few harmful pathologies mammals. The present article will review potential roles key player different cells T B lymphocytes, macrophages, dendritic killer antiviral activity.

Language: Английский

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Los olvidados: Non-BRCA variants associated with Hereditary breast cancer in Mexican population

Breast Cancer Research, Journal Year: 2025, Volume and Issue: 27(1)

Published: Jan. 15, 2025

Abstract Background Hereditary predisposition to breast and ovarian cancer syndrome (HBOC) is a pathological condition with increased risk, including (BC), (OC), others. HBOC pathogenesis caused mainly by germline pathogenic variants (GPV) in BRCA1 BRCA2 genes. However, other relevant genes are related this diagnosis, prognosis, treatment, TP53 , PALB2 CHEK2 ATM etc. This study aimed identify the prevalence of non- BRCA patients Northeast Mexico. Methods multicentric included 1285 diagnosis from four oncologic centers northeast Mexico 2016 2023. Genomic clinical data were analyzed based on multi-gene panel results electronic records medical geneticist consultation. For analysis qualitative quantitative variants, JASP statistical software (version 0.18.1) was used, taking p < 0.05 as significant result. Results We found that 32.7% had at least one GPV The five most frequent MUTYH CDKN2A . Among group genes, six involved homologous repair pathway (HR), three DNA damage (DDR) pathways. In analyzing GPVs molecular pathways, both have similar frequencies no difference for BC. Conclusion Multi-gene testing implementation improves detection often overlooked treatment. Non- Northern correspond one-third cases, HR DDR pathways would be misdiagnosed if not tested. patient carriers potential targets iPARP therapies. optimal approach treatment mutation warrants further investigation develop newer

Language: Английский

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