Correlation of BARD1 gene polymorphisms with risk of neuroblastoma: a meta-analysis.

BRCA1-associated RING domain protein 1 (BARD1) gene polymorphisms may be associated with neuroblastoma (NB) susceptibility. However, the results remain controversial. Relevant studies were identified by searching PubMed, Web of Science, Embase, China National Knowledge Infrastructure databases up to March 5, 2023. The strength of the association between BARD1 polymorphisms and susceptibility of NB was assessed by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs) through the fixed- or random-effects model. Eight articles involving 12 studies were finally included. We found that rs6435862 T > G, rs3768716 A > G, rs17487792 C > T and rs7587476 C > T variant increase the risk of NB in allelic, dominant, recessive, homozygous and heterozygous genetic models, while rs7585356 G > A variant appeared protective against NB. When stratified by ethnicity, subgroup analysis indicated that the above association remained significant in Caucasian populations in all genetic models, except for rs7585356G > A polymorphism in Asians. In Asian populations, we found the similar results in the allelic and dominant model of rs6435862 T > G, rs3768716 A > G, rs17487792 C > T and rs7587476 C > T as in Caucasians, while there lacked a significant association in the other three model. In addition, rs7585356 G > A was not associated with an increased risk of NB in the Asian population. After Bonferroni correction, significant associations for rs7585356 G > A disappeared in both Asian and Caucasian populations, with no significant association found for rs7587476 in the allelic and dominant models among Asians. BARD1 polymorphisms might be significantly associated with NB susceptibility. It is crucial that these finding should be further confirmed through extensive and well-planned studies.

BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.

The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors.

Mechanisms of RNF168 nucleosome recognition and ubiquitylation.

RNF168 plays a central role in the DNA damage response (DDR) by ubiquitylating histone H2A at K13 and K15. These modifications direct BRCA1-BARD1 and 53BP1 foci formation in chromatin, essential for cell-cycle-dependent DNA double-strand break (DSB) repair pathway selection. The mechanism by which RNF168 catalyzes the targeted accumulation of H2A ubiquitin conjugates to form repair foci around DSBs remains unclear. Here, using cryoelectron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy, and functional assays, we provide a molecular description of the reaction cycle and dynamics of RNF168 as it modifies the nucleosome and recognizes its ubiquitylation products. We demonstrate an interaction of a canonical ubiquitin-binding domain within full-length RNF168, which not only engages ubiquitin but also the nucleosome surface, clarifying how such site-specific ubiquitin recognition propels a signal amplification loop. Beyond offering mechanistic insights into a key DDR protein, our study aids in understanding site specificity in both generating and interpreting chromatin ubiquitylation.

IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors.

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.

CellTool: An Open-Source Software Combining Bio-Image Analysis and Mathematical Modeling for the Study of DNA Repair Dynamics.

Elucidating the dynamics of DNA repair proteins is essential to understanding the mechanisms that preserve genomic stability and prevent carcinogenesis. However, the measurement and modeling of protein dynamics at DNA lesions via currently available image analysis tools is cumbersome. Therefore, we developed CellTool-a stand-alone open-source software with a graphical user interface for the analysis of time-lapse microscopy images. It combines data management, image processing, mathematical modeling, and graphical presentation of data in a single package. Multiple image filters, segmentation, and particle tracking algorithms, combined with direct visualization of the obtained results, make CellTool an ideal application for the comprehensive analysis of DNA repair protein dynamics. This software enables the fitting of obtained kinetic data to predefined or custom mathematical models. Importantly, CellTool provides a platform for easy implementation of custom image analysis packages written in a variety of programing languages. Using CellTool, we demonstrate that the ALKB homolog 2 (ALKBH2) demethylase is excluded from DNA damage sites despite recruitment of its putative interaction partner proliferating cell nuclear antigen (PCNA). Further, CellTool facilitates the straightforward fluorescence recovery after photobleaching (FRAP) analysis of BRCA1 associated RING domain 1 (BARD1) exchange at complex DNA lesions. In summary, the software presented herein enables the time-efficient analysis of a wide range of time-lapse microscopy experiments through a user-friendly interface.

Genomic Alterations of Signaling and DNA Damage Repair Pathways in Non-Muscle Invasive Bladder Cancer.

The aim of the study was to demonstrate the most common genetic alterations and evaluate possible targets involving phosphatidylinositol-3-OH kinase (PIK3)/AKT/mammalian target of rapamycin (mTOR) signaling and DNA damage repair (DDR) pathways for personalized treatment in patients with non-muscle invasive bladder cancer (NMIBC). Alterations of these pathways were observed in 89.5% and 100% of patients, respectively. Among them, BARD1 was more frequently altered in low/intermediate-risk cases, but PARP4 was more frequently affected in intermediate/high-risk patients. The possible target feasibility of BARD1 and PARP4 alterations should be evaluated for personalized treatment using PARP-inhibitors in NMIBC. It is important to detect high tumor mutation burden (TMB) in patients in terms of immunotherapy.

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

Combining single-cell sequencing and spatial transcriptome sequencing to identify exosome-related features of glioblastoma and constructing a prognostic model to identify BARD1 as a potential therapeutic target for GBM patients.

Background: Glioblastoma (GBM) is a malignant primary brain tumor. This study focused on exploring the exosome-related features of glioblastoma to better understand its cellular composition and molecular characteristics. Methods: Single-cell RNA sequencing (scRNA-seq) and spatial transcriptome RNA sequencing (stRNA-seq) were used to analyze the heterogeneity of glioblastomas. After data integration, cell clustering, and annotation, five algorithms were used to calculate scores for exosome-related genes(ERGs). Cell trajectory analysis and intercellular communication analysis were performed to explore exosome-related communication patterns. Spatial transcriptome sequencing data were analyzed to validate the findings. To further utilize exosome-related features to aid in clinical decision-making, a prognostic model was constructed using GBM's bulk RNA-seq. Results: Different cell subpopulations were observed in GBM, with Monocytes/macrophages and malignant cells in tumor samples showing higher exosome-related scores. After identifying differentially expressed ERGs in malignant cells, pseudotime analysis revealed the cellular status of malignant cells during development. Intercellular communication analysis highlighted signaling pathways and ligand-receptor interactions. Spatial transcriptome sequencing confirmed the high expression of exosome-related gene features in the tumor core region. A prognostic model based on six ERGs was shown to be predictive of overall survival and immunotherapy outcome in GBM patients. Finally, based on the results of scRNA-seq and prognostic modeling as well as a series of cell function experiments, BARD1 was identified as a novel target for the treatment of GBM. Conclusion: This study provides a comprehensive understanding of the exosome-related features of GBM in both scRNA-seq and stRNA-seq, with malignant cells with higher exosome-related scores exhibiting stronger communication with Monocytes/macrophages. In terms of spatial data, highly scored malignant cells were also concentrated in the tumor core region. In bulk RNA-seq, patients with a high exosome-related index exhibited an immunosuppressive microenvironment, which was accompanied by a worse prognosis as well as immunotherapy outcomes. Prognostic models constructed using ERGs are expected to be independent prognostic indicators for GBM patients, with potential implications for personalized treatment strategies for GBM. Knockdown of BARD1 in GBM cell lines reduces the invasive and value-added capacity of tumor cells, and thus BARD1-positively expressing malignant cells are a risk factor for GBM patients.

Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Association of BARD1 and BRIP1 Gene Polymorphisms with the Risk of Uveal Melanoma.

Considering the limited information about the role of hereditary predisposition to the development of uveal melanoma, we have performed an analysis of the frequencies of BARD1 (rs1048108, rs2229571, rs2070094) and BRIP1 (rs4986764) gene polymorphisms in patients with uveal melanoma and benign choroidal nevus in comparison with healthy volunteers (control). It has been found that the minor alleles of BRIP1 rs4986764 and BARD1 rs2070094 polymorphisms, as well as the homozygosity of T allele at the BARD1 rs1048108 locus are common genetic markers for the predisposition to uveal melanoma and benign choroidal nevus, while the homozygous genotype GG for the BARD1 rs2229571 polymorphism is a specific marker for the predisposition to uveal melanoma and progressive choroidal nevus. We have also found that the heterozygous genotype at BARD1 rs1048108 polymorphic locus is a specific marker for protection against uveal melanoma and progressive choroidal nevus. Thus, our results indicate the advisability of studying polymorphisms of the BARD1 gene (rs1048108, rs2229571, and rs2070094) and the BRIP1 gene (rs4986764) in patients with uveal melanoma and progressive choroidal nevus. The obtained findings can be used for forming risk groups, prevention of uveal melanoma, and differential diagnosis of intraocular neoplasms.

Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report.

Despite advances in the treatment of high-risk neuroblastoma, approximately half of these patients die from the disease. Targeted therapy based on synthetic lethality associated with homologous recombination deficiency (HRD) caused by germline mutations in homologous recombination repair genes has shown great efficacy in several adult solid tumors. Here we report the first successful treatment of a pediatric patient with refractory neuroblastoma and a germline pathogenic mutation in BARD1 using a PARP inhibitor, talazoparib, in combination with cytotoxic chemotherapy and radiation therapy. Allele-specific expression in RNA-seq indicates bi-allelic loss of BARD1 in tumor; however, the HRD score was below the threshold currently used for HRD classification in adult cancers. Our study demonstrates that the use of PARP inhibition in combination with DNA-damaging agents should be considered in children with BARD1-mutated neuroblastoma and cautions against the use of HRD score alone as a biomarker for this pediatric population.

Structural dynamics of clinically-reported VUS in the BARD1 ARD-BRCT region to predict the molecular basis of alterations.

The functional domains of BARD1, comprise the Ankyrin Repeat Domain (ARD), C-Terminal domains (BRCTs), and a linker between ARD and the BRCTs, which are known to bind to Cleavage stimulation Factor complex-subunit of 50 kDa (CstF-50). The pathogenic mutation Q564H in the BARD1 ARD-linker-BRCT region has been reported to abrogate the binding between BARD1 and CstF-50. Intermediate penetrance variants of BARD1 are associated with the occurrence of breast cancer. Therefore, seven missense variants of unknown significance (VUS), L447V, P454L, N470S, V507M, I509T, C557S, and Q564H of BARD1, reported in the ARD domain and the linker region were evaluated via molecular dynamics (MD) simulations. The mutants revealed statistically significantly different distributions of RMSD (root mean square deviation), residuewise RMSF (root mean square fluctuation), Rg (radius of gyration), SASA (solvent accessible surface area), and COM (centre of mass)-to-COM distance between the ARD and the BRCT repeat, between the wild type and each mutant. The secondary structural composition of the mutants was slightly altered relative to that of the wild type. However, the reported in-silico based prediction require further validation using in-vitro, biophysical and structure-based approachCommunicated by Ramaswamy H. Sarma.

BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.

BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.

In silico investigation on the mutational analysis of BRCA1-BARD1 RING domains and its effect on nucleosome recognition and ubiquitination.

The BRCA1-BARD1 complex is a crucial tumor suppressor E3 ubiquitin ligase involved in DNA double-stranded break repair. The BRCA1-BARD1 RING domains interact with UBE2D3 through the BRCA1 interface and this complex flexibly tether to the nucleosome core particle (NCP), where BRCA1 and BARD1 interacts with histone H2A and H2B of NCP. Mutations in the BRCA1-BARD1 RING domains have been linked to familial breast and ovarian cancer. Seven mutations were analyzed to understand their effect on the binding interface of protein partners and changes in conformational dynamics. Molecular dynamics simulations revealed that mutant complexes were less conformationally flexible than the wildtype complex. Protein-protein interaction profiling showed the importance of specific molecular interactions, hotspot and hub residues, and some of these were lost in the mutant complexes. Two mutations (BRCA1L51W-K65R and BARD1C53W) hindered significant interaction between protein partners and may prevent signaling for ubiquitination of histones in NCP and other cellular targets. The structural compactness and reduced significant interaction in mutant complexes may be the possible reason of preventing ubiquitination and hinder DNA repair, resulting cancer.

Germline heterozygous exons 8-11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?

BACKGROUND: Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear. CASE PRESENTATION: We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease. CONCLUSIONS: To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health.

Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma.

Ewing sarcoma is a fusion oncoprotein-driven primary bone tumor. A subset of patients (~10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. We thus questioned the impact of BARD1 loss on Ewing cell sensitivity to DNA damage and the Ewing sarcoma transcriptome. We demonstrate that PSaRC318 cells, a novel patient-derived cell line harboring a pathogenic BARD1 variant, are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that BARD1 loss enhances cell sensitivity to PARP inhibition plus radiation. Additionally, RNA-seq analysis revealed that loss of BARD1 results in the upregulation of GBP1 (guanylate-binding protein 1), a protein whose expression is associated with variable response to therapy depending on the adult carcinoma subtype examined. Here, we demonstrate that GBP1 contributes to the enhanced sensitivity of BARD1 deficient Ewing cells to DNA damage. Together, our findings demonstrate the impact of loss-of function mutations in DNA damage repair genes, such as BARD1, on Ewing sarcoma treatment response.

[Progress in atypical ubiquitination via K6-linkages].

Ubiquitination is a post-translational modification of proteins in eukaryotes, which mediates the specific degradation and signal transduction of proteins to regulate a variety of life processes and thus affects functions of the body. The disorder and imbalance of ubiquitination network is a major cause of serious human diseases. Ubiquitin molecules can form eight homogeneous ubiquitin chains with different topological structures, which vary greatly in abundance and function. At present, the classical ubiquitin chains K48 and K63 with high abundance and rich substrates have been intensively studied, while other atypical ubiquitin chains with low content remain to be studied. However, it has been proved that atypical ubiquitin chains play a key role in intracellular regulation. K6 is an important atypical ubiquitin chain, which is similar to K48 chain and has a tight spatial structure. It plays a role in DNA damage repair, mitochondrial quality control, the occurrence and development of tumor, and the pathogenesis of Parkinson's disease. Due to the lack of specific antibodies and effective enrichment methods for K6, little is known about its substrate and regulatory mechanism. This paper systematically reviews the structural characteristics, regulatory mechanism, biological functions, and relevant diseases of atypical K6 linkages, aiming to provide reference for the functional study of K6.

Decoding histone ubiquitylation.

Histone ubiquitylation is a critical part of both active and repressed transcriptional states, and lies at the heart of DNA damage repair signaling. The histone residues targeted for ubiquitylation are often highly conserved through evolution, and extensive functional studies of the enzymes that catalyze the ubiquitylation and de-ubiquitylation of histones have revealed key roles linked to cell growth and division, development, and disease in model systems ranging from yeast to human cells. Nonetheless, the downstream consequences of these modifications have only recently begun to be appreciated on a molecular level. Here we review the structure and function of proteins that act as effectors or "readers" of histone ubiquitylation. We highlight lessons learned about how ubiquitin recognition lends specificity and function to intermolecular interactions in the context of transcription and DNA repair, as well as what this might mean for how we think about histone modifications more broadly.

BARD1 mystery: tumor suppressors are cancer susceptibility genes.

The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment.