Search Results (243)

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage recognition and repair, therefore impairing homologous recombination (HR), non-homologous end joining (NHEJ), and base excision repair (BER) by suppressing key repair genes and lowering access to repair sites. Then it is dissected how loss-of-function mutations in Switch/Sucrose non-fermentable, imitation switch and CHD (Chromodomain helicase DNA-binding) chromatin-remodeling complexes impair nucleosome repositioning, preventing effective damage sensing and assembly of repair machinery. Non-coding RNAs contribute to epigenetic silencing at DNA break sites, exacerbating repair deficiencies. This review evaluates recent advances concerning epigenetic dysfunction and DNA repair impairment. It is also highlighted that nanoparticle-mediated delivery strategies are designed to overcome pharmacologic resistance. It is presented how epigenetic dysregulation of DNA repair can guide more effective and drug-resistant cancer therapies. Full article

Hereditary breast and ovarian cancer (HBOC) syndrome is primarily associated with mutations in BRCA1 and BRCA2, but increasing evidence links it to other malignancies, including male breast, prostate, and pancreatic cancers. Advances in genetic testing have led to the use of multigene panels, revealing that additional genes contribute to HBOC risk. We tested 280 patients with suspected HBOC using a multigene panel including BRCA1, BRCA2, and other genes involved in homologous recombination (HR) and additional DNA repair mechanisms. Variants were classified as pathogenic variants (PVs), variants of uncertain significance (VUS), or novel. In silico tools were used to predict the clinical relevance of VUS and novel variants. The clinical phenotype of families carrying a PV was evaluated. PVs were identified in 19.3% of patients: 8.9% in BRCA1/2 and 10.4% in other genes, mainly CHEK2, ATM, PALB2, and BRIP1. An additional 1.8% of cases harbored likely pathogenic VUS or novel variants according to bioinformatic prediction. Breast and ovarian cancer were the most frequent malignancies in our population, both in the BRCA group and in those with PVs in other susceptibility genes. Broad genetic testing beyond BRCA improves HBOC diagnostics, supports identification of at-risk families, and enables more personalized surveillance and treatment. Full article

Trichomonas vaginalis, the protozoan responsible for trichomoniasis, encounters fluctuating levels of metal cations in the male urogenital tract, notably zinc (Zn²⁺) and cadmium (Cd²⁺), which may induce genotoxic stress. While zinc is a key physiological component of the male reproductive tract, both Zn²⁺ and Cd²⁺ can become genotoxic at elevated concentrations. However, their effect on DNA repair mechanisms in T. vaginalis remains poorly understood. This study characterizes, for the first time, the expression and modulation of the recombinase TvRAD51, a homologous recombination (HR) key enzyme, in response to UV irradiation and sublethal concentrations of Zn²⁺ (1.6 mM) and Cd²⁺ (0.1 mM). In silico analyses confirmed the presence and conserved structure of the tvrad51 gene and its interaction with HR-related proteins, such as TvBLM and TvBRCA2. Quantitative RT-PCR, Western blot, and immunofluorescence assays revealed that TvRAD51 is upregulated at both transcript and protein levels following UV- and cation-induced DNA damage, with distinct temporal expression patterns for Zn²⁺ and Cd²⁺ exposure. Notably, TvRAD51 showed nuclear localization at early time points post-exposure, suggesting active participation in DNA repair processes. These findings demonstrate that TvRAD51 is a central component of the genotoxic stress response in T. vaginalis, potentially contributing to parasite survival and adaptation in hostile environments through homologous recombination repair pathways. Full article

Fusarium acuminatum is a major pathogenic fungus causing root rot in alfalfa (Medicago sativa). DNA polymerase theta is known to play a crucial role in repairing DNA double-strand breaks. However, its biological function in F. acuminatum remains unknown. In this study, the POLQ gene was deleted by homologous recombination using Agrobacterium tumefaciens-mediated transformation. Compared to the wild type (with the POLQ gene), the mutants (without the POLQ gene) showed significant phenotypic changes: they produced brown-yellow pigments instead of pink, slowed mycelial growth, and exhibited changes in macroconidia size and shape. The virulence of the mutants was greatly reduced, inducing only mild symptoms in alfalfa. In addition, FITC-WGA staining showed impaired spore germination and hyphal growth. These results suggest that POLQ is a key gene regulating growth and development of F. acuminatum, indicating that DNA repair may play an essential role in the pathogenicity of the pathogen in alfalfa. The POLQ gene could thus be a promising target for limiting F. acuminatum infections in alfalfa. Full article

The genotoxic drug doxorubicin (Dox) remains one of the most powerful chemotherapeutic options available for a wide range of cancers including breast, ovarian, and other cancers. However, emerging evidence links Dox treatment with chemotherapy-induced cognitive impairment, a condition that is popularly referred to as Dox-induced neurotoxicity or “chemobrain”, which limits the use of the drug. There are no specific treatments for Dox-induced neurotoxicity, only interventions to mitigate the neurotoxic effects of the drug. Accumulating evidence indicates that DNA damage, oxidative stress, dysregulation of autophagy and neurogenesis, inflammation, and apoptosis play central roles in Dox-induced neurotoxicity. Additionally, germline mutations in the tumour suppressor genes breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) increase the risk of breast, ovarian, and related cancers. BRCA1 and BRCA2 are distinct proteins that play crucial, unique roles in homologous recombination-mediated double-stranded break repair. Furthermore, BRCA1 and 2 mitigate oxidative stress in both neural cells and brain microvascular endothelial cells, which suggests that they have a critical role as regulators of pathways central to the development of Dox-induced neurotoxicity. Despite research on the effects of Dox on cognitive function, there is a gap in knowledge about the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity. In this review, we discuss existing findings about the role of different mechanisms and the role of BRCA1 and BRCA2 in Dox-induced neurotoxicity, along with future perspectives. Full article

Purpose: To determine if the risk of clonal hematopoiesis (CH) would be higher among those with germline alterations in homologous recombination repair genes (gHRR) in the four BRCA-associated cancers (breast, ovarian, prostate, pancreas) compared to those without inherited predisposition (the sporadic group). Methods: We retrospectively analyzed deidentified data from 24,849 patient samples from the Tempus database with a primary diagnosis of breast, ovarian, prostate, and pancreatic cancers. Germline pathogenic or likely pathogenic variants in BRCA1, BRCA2, ATM, PALB2, and CHEK2 were identified across all four cancer types. CH was determined based on the presence of pathogenic or likely pathogenic alterations in any one of 52 CH-associated genes with a variant allele fraction of at least 2% found in the normal match. Age-adjusted odds ratios were calculated for risk of CH across cancer types. Results: CH was identified in 14% of patients with BRCA-associated cancers. DNMT3A, PPM1D, and TET2 were the most common CH gene alterations. After adjusting for age at time of biopsy, having any germline alteration in the breast cancer cohort was associated with a 41% increased likelihood of CH (OR 1.41; 95% CI 1.07–1.84, p = 0.014). An increase in CH prevalence was not seen in the three other cancer types. Conclusions: When accounting for age at time of testing, pathogenic germline alterations in DNA repair genes were associated with an increased risk of CH only among patients with breast cancer, but not in those with ovarian, pancreatic, or prostate cancers. Full article

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests that BRCA1 is an essential driver of all phases of the cell cycle, thereby maintaining orderly steps during cell cycle progression. Specifically, loss of BRCA1 activity causes the S-phase, G₂/M, spindle checkpoints, and centrosome duplication to be dysregulated, thereby blocking cell proliferation and inducing apoptosis. In vertebrates, loss of HR genes such as BRCA1 and/or BRCA2 is lethal, since HR is a prerequisite for genome integrity. Thus, cancer cells utilize alternative DNA repair pathways such as non-homologous end joining (NHEJ) to cope with the loss of BRCA1 function. In this review, we attempt to update and discuss how these novel components are crucial for regulating DNA damage repair (DDR) in BRCA1-deficient cancers. Full article

Recent evidence indicates that FAM111B is significantly involved in the progression of various cancers. Nonetheless, the potential pan-cancer implications of FAM111B have not been systematically investigated. In this study, FAM111B’s expression and oncogenic potential were studied using TCGA and GTEx data via GEPIA2, TIMER2.0, and STRING tools. Pathway enrichment analyses with the GO, KEGG, Reactome, and WikiPathways databases were conducted to explore its role in cancer development. The results were validated via multiplex immunofluorescence assays of pancreatic cancer tissues, microarray assays of ovarian cancer tissues, and protein transcriptomics of ovarian cancer cells. The expression levels of FAM111B were elevated in most cancer types and were associated with poor prognostic outcomes. Mechanistically, FAM111B expression was positively correlated with the expression of genes involved in DNA homologous recombination repair and with the infiltration of Th2 CD4+ T cells. These observations were further substantiated in ovarian cancer cell lines and tissue specimens from pancreatic and ovarian cancers. FAM111B functions as a biomarker for the DNA repair pathway and Th2 CD4+ T-cell infiltration in human malignancies. Full article

This study investigated whether combining niraparib and trabectedin in BRCA-proficient epithelial ovarian cancer induces deficiencies in ssDNA break repair and dsDNA homologous recombination, leading to synthetic lethality. A2780 and SKOV3 ovarian cancer cell lines were treated with niraparib and trabectedin. Cell viability was assessed using CCK-8 assays, while RT-qPCR and Western blot analyzed the expression of DNA repair and apoptosis-related genes. Apoptosis was evaluated via Annexin V/PI assays. The combination therapy exhibited a synergistic effect on A2780 cells but not on SKOV3 cells. Treatment reduced BRCA1, BRCA2, RAD51, PARP1, and PARP2 expression, indicating impaired DNA repair. γ-H2AX levels increased, suggesting DNA damage. The therapy also upregulated p53, PUMA, NOXA, BAX, BAK, and p21, promoting p53-mediated apoptosis and cell cycle arrest. Apoptosis induction was confirmed via Annexin V/PI assays. Silencing p53 with siRNA abolished all synergistic effects in A2780 cells. Niraparib and trabectedin combination therapy impairs DNA repair in BRCA-proficient ovarian cancer, leading to synthetic lethality through p53-dependent apoptosis. Full article

Colorectal cancer (CRC) is a highly heterogeneous gastrointestinal malignancy. Despite significant advances in molecular targeted therapies for CRC in recent years, the increase in the overall survival rates for CRC patients remains limited. Therefore, there is an urgent need to explore novel drug targets. Herein, we show that heparin binding growth factor (HDGF) is highly expressed in CRC, and that its overexpression is associated with a poor disease-free interval. Additionally, we reveal that HDGF knockout reduces proliferation, migration, and invasion, while enhancing apoptosis in CRC cells, thereby validating HDGF as a potential therapeutic target for CRC. Mechanistically, we found that HDGF modulates DNA damage response and, by recruiting C-terminal binding protein-interacting protein (CtIP), it facilitates homologous recombination repair to influence CRC drug sensitivity. Furthermore, we propose that HDGF may serve as a recognition protein for H3K36me3, participating in the repair of damaged transcriptionally active genes, thus maintaining genomic stability in CRC. Full article

Meiotic recombination is initiated by the formation of programmed DNA double-strand breaks during spermatogenesis. PRDM9 determines the localization of recombination hotspots by interacting with several protein complexes in mammals. The function of PRDM9 is not well understood during spermatogenesis in mice or yaks. In this study, we applied yeast two-hybrid assays combined with next-generation sequencing techniques to screen the complete set of PRDM9-interacting proteins and explore its novel functions in yak spermatogenesis. Our results showed that 267 PRDM9-interacting proteins were identified. The gene ontology (GO) analysis of the interacting proteins revealed that the GO terms were primarily associated with spermatogenesis, positive regulation of double-strand break repair via homologous recombination, RNA splicing, the ubiquitin-dependent ERAD pathway, and other biological processes. MKX and PDCD5 were verified to be strongly interacting with PRDM9 and expressed in prophase I of meiosis in both mouse and yak testes. The localizations of RNA splicing genes including THOC5, DDX5, and XRCC6 were expressed in spermatocytes. Cattleyak is the hybrid offspring of a yak and a domestic cow, and the male offspring are sterile. The gene expression of the interacting proteins was also examined in the sterile male hybrid of yak and cattle. Among the 58 detected genes, 55 were downregulated in cattleyak. In conclusion, we established a complete PRDM9 interaction network, and a novel function of PRDM9 was identified, which will further promote our understanding of spermatogenesis. It also provides new insights for the study of hybrid male sterility. Full article

It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient’s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1. Full article

RAD18 is a conserved eukaryotic E3 ubiquitin ligase that promotes genome stability through multiple pathways. One of these is gap-filling DNA synthesis at active replication forks and in post-replicative DNA. RAD18 also regulates homologous recombination (HR) repair of DNA breaks; however, the current literature describing the contribution of RAD18 to HR in mammalian systems has not reached a consensus. To investigate this, we examined three independent RAD18-null human cell lines. Our analyses found that loss of RAD18 in HCT116, but neither hTERT RPE-1 nor DLD1 cell lines, resulted in elevated sister chromatid exchange, gene conversion, and gene targeting, i.e., HCT116 mutants were hyper-recombinogenic (hyper-rec). Interestingly, these phenotypes were linked to RAD18’s role in PCNA K164 ubiquitination, as HCT116 PCNA^K164R/+ mutants were also hyper-rec, consistent with previous studies in rad18^−/− and pcna^K164R avian DT40 cells. Importantly, the knockdown of UBC9 to prevent PCNA K164 SUMOylation did not affect hyper-recombination, strengthening the link between increased recombination and RAD18-catalyzed PCNA K164 ubiquitination, but not K164 SUMOylation. We propose that the hierarchy of post-replicative repair and HR, intrinsic to each cell type, dictates whether RAD18 is required for suppression of hyper-recombination and that this function is linked to PCNA K164 ubiquitination. Full article

The methylotrophic yeast Komagataella kurtzmanii belongs to the group of homothallic fungi that are able to spontaneously change their mating type by inversion of chromosomal DNA in the MAT locus region. As a result, natural and genetically engineered cultures of these yeasts typically contain a mixture of sexually dimorphic cells that are prone to self-diploidisation and spore formation accompanied by genetic rearrangements. These characteristics pose a significant challenge to the development of genetically stable producers for industrial use. In the present study, we constructed heterothallic strains of K. kurtzmanii, ensuring a constant mating type by unifying the genetic sequences in the active and silent MAT loci. To obtain such strains, we performed site-directed inactivation of one of the two yeast MAT loci, replacing its sequence with a selective HIS4 gene surrounded by I-SceI meganuclease recognition sites. We then used transient expression of the SCE1 gene, encoding a recombinant I-SceI meganuclease, to induce site-specific cleavage of HIS4, followed by damage repair by homologous recombination in mutant cells. As a result, heterothallic strains designated ‘Y-727-2(alpha)’ and ‘Y-727-9(a)’, which correspond to the α and a mating type, respectively, were obtained. The strains demonstrated a loss of the ability to self-diploidize. The results of PCR and whole genome analysis confirmed the identity of the contents of the MAT loci. Analysis of the genomes of the final strains, however, revealed a fusion of chromosome 3 and chromosome 4 in strain Y-727-2(alpha)-1. This finding was subsequently confirmed by pulsed-field gel electrophoresis of yeast chromosomes. However, the ability of the Y-727-2(alpha)-derived producers to efficiently secrete recombinant β-galactosidase was unaffected by this genomic rearrangement. Full article