Interacting Protein C-terminal Helicase Research Articles

Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: a pan-cancer analysis

BackgroundThe aberrant expression of BRIP1 was associated with several cancers; however, the panoramic picture of BRIP1 in human tumors remains unclear. This study aims to explore the pan-cancerous picture of the expression of BRIP1 across 33 human cancers.MethodsBased on the data from TCGA and GTEx, a series of bioinformatic analyses were applied to systematically explore the genetic landscape and biologic function of BRIP1 in 33 human tumors.ResultsWe observed prognosis-related differential BRIP1 expressions between various carcinomas and the corresponding normal tissues. “Basal transcription factors,” “homologous recombination,” “nucleotide excision repair,” and DNA metabolism pathways may play a role in the functional mechanisms of BRIP1. Patients with uterine corpus endometrial carcinoma presented with the highest alteration frequency of BRIP1 (nearly 10%). Single-nucleotide and copy number variations of BRIP1 were noticed in multiple cancers, and the expression of BRIP1 is significantly regulated by copy number variation in breast invasive carcinoma and lung squamous cell carcinoma. BRIP1 expression is negatively correlated with the DNA methylation levels in many tumors and is associated with the activation of apoptosis, cell cycle, DNA damage response, and inhibition of hormone ER and RNS/MARK signaling pathways. Moreover, a positive correlation was observed between BRIP1 expression and the immune infiltration levels of cancer-associated fibroblasts and CD8+ T cells in lung adenocarcinoma.ConclusionOur pan-cancer analysis of BRIP1 provides a valuable resource for understanding the multimolecular characteristics and biological function of BRIP1 across human cancers.

Comparative genomics and selection analysis of Yeonsan Ogye black chicken with whole-genome sequencing.

Yeonsan Ogye (OGYE; Gallus gallus domesticus) is a rare indigenous chicken breed that inhabits the Korean Peninsula. This breed has completely black coloring, including plumage, skin, eyes, beak, and internal organs. Despite these unique morphological characteristics, the population of OGYE has declined without in-depth research into their genome research. Therefore, this study aimed to compare the whole genome of OGYE to 12 other chicken populations, including ancestral breed, commercial breeds, Chinese indigenous breeds, and Korean native chickens. We focused on revealing the selection signature of OGYE, which has occurred through environmental pressures in the Korean Peninsula. Genome-wide selection analysis has identified local adaptation traits, such as egg development, that contribute to fetal viability and innate immune response to prevent viral and microbes infection in OGYE. In particular, SPP1 (Secreted Phosphoprotein 1), HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1), and P2RX4 (Purinergic Receptor P2X 4) could have considerable involvement in egg development and RNASEL (Ribonuclease L), BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1), and TLR4 (Toll-Like Receptor 4) are crucial for the determination of the innate immune response. This study revealed the unique genetic diversity of OGYE at the genome-wide level. Furthermore, we emphasized the sustainable management of genetic resources and formulated breeding strategies for livestock on the Korean Peninsula.

Calycosin stimulates the proliferation of endothelial cells, but not breast cancer cells, via a feedback loop involving RP11-65M17.3, BRIP1 and ERα.

It is widely accepted that estrogen can be replaced by phytoestrogens to treat postmenopausal cardiovascular disease and possibly decrease the risk of breast cancer. However, few studies have investigated the effects of phytoestrogens on vascular endothelial cells (ECs). In the present study, we show that the phytoestrogen calycosin (20 μM) stimulated the proliferation of ECs (HUVECs and HMEC-1) but inhibited the growth of breast cancer cells (BCCs) expressing ERα (MCF-7 and T47D). Here we provide evidence for the presence of a positive feedback loop between ERα and long noncoding RNA RP11-65M17.3 in both normal and cancer cells, and calycosin stimulated this feedback loop in ECs but decreased RP11-65M17.3 expression in BCCs. Subsequently, the calycosin-induced activation of this loop decreased the expression of the target of BRIP1 (BRCA1 interacting protein C-terminal helicase 1), increased the phosphorylation of Akt and ERK1/2, and finally inhibited the cleavage of PARP-1 in ECs. In nude mice bearing MCF-7 xenografts, calycosin did not stimulate tumor growth as strongly as 17β-estradiol. Together, these results suggest that calycosin promotes the proliferation of ECs, and notable inhibits the growth of BCCs. A possible reason for these results is the involvement of a feedback loop between ERα and RP11-65M17.3.

Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells

ObjectivePathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity. MethodsWe engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices. ResultsBRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality. ConclusionsBRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.

BRIP1 rs10744996C>A variant increases the risk of chronic obstructive pulmonary disease in the Mongolian population of northern China.

What is the central question of this study? What is the role of breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) polymorphism in chronic obstructive pulmonary disease (COPD)? What is the main finding and its importance? Variant rs10744996C>A of BRIP1 increases the susceptibility of the Mongolian population to COPD. The expression of BRIP1 was significantly reduced in cigarette smoke extract-treated airway epithelial cells. Cigarette smoke is a major environmental pollutant that can induce DNA damage in humans. The development and progression of chronic obstructive pulmonary disease (COPD) are known to be related to the impairment of DNA repair. Breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) plays an important role in DNA interstrand crosslink repair and double-strand break repair. However, the role of BRIP1 polymorphisms in COPD has not been previously described. In this study, whole genome sequencing was used to identify mutations, and single nucleotide polymorphism (SNP) genotyping was used to verify the selected SNPs. In addition the BRIP1 expression levels in 16HBE and A549 airway epithelial cells treated with or without cigarette smoke extract (CSE) were measured using western blotting and RT-qPCR. Rs10744996C>A in the 3'-untranslated region (3'UTR) of BRIP1 was then genotyped in 1296 COPD cases and 988 healthy control subjects from a Mongolian population in northern China. Significant differences in the distribution of rs10744996C>A variants between COPD and control groups (P=0.001) were identified. Rs10744996C>A was found to be associated with significantly increased COPD risk (adjusted odds ratio=1.60, 95% CI=1.30-1.98, P<0.0001). Additionally, rs10744996A genotype was found to interact with a family history of cancer and a history of x-ray exposure (P=0.028 and 0.009, respectively). BRIP1 expression levels in 16HBE and A549 cells treated with CSE were significantly lower compared to the control treated cells. The rs10744996C>A variant of BRIP1 increased the COPD susceptibility of the Mongolian population cohort. BRIP1 mRNA and protein expression levels were significantly reduced in conjunction with CSE-induced DNA damage in 16HBE and A549 cells.

Abstract P6-08-31: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) as a cancer susceptibility gene

Abstract Background: Breast cancer is the most common cancer as well as the most common cause of cancer associated deaths in women worldwide. National Comprehensive Cancer Network has detailed criteria for identifying patients at risk for hereditary breast and ovarian cancer syndromes. Many multigene genetic testing panels are in use for screening and prognostication purposes. While pathogenic mutation in BRCA 1 and 2 mutations have been established as risk factors for developing breast cancer, the association of other germ line mutations with breast cancer is less defined. BRCA1 interacting protein C-terminal helicase 1 (BRIP1) influences the DNA repair ability as well as tumor suppressor function of BRCA1 and is associated with increased risk of ovarian cancer. Studies looking at association of BRIP1 mutation with risk of breast cancer have provided conflicting data and currently, BRIP1 is not implicated in causing breast cancer. Methods: We conducted chart review of patients who were referred for genetic testing at the Lipson Cancer Institute/Rochester General Hospital, Rochester, NY and tested positive for BRIP1 mutation alone. Samples were sent to Myriad Genetics for Integrated BRACAnalysis® testing with myRisk® panel looking at 35 genes for mutation. BRIP1 mutations with abnormal protein production and/or function thought to increase risk for ovarian cancer (pathogenic or likely pathogenic) are reported as clinically significant. BRIP1 mutations with currently insufficient data to determine an increased risk are reported as variations of uncertain significance. The panel does not report benign and likely benign mutations. Results: We found nine patients who tested positive for BRIP1 mutation and were negative for other genomic alteration including BRCA1 and BRCA2 mutation (Table 1 and 2). Four patients carried the known high risk BRIP1 mutation and five carried BRIP1 mutations of undetermined significance. One of four patients with known high risk BRIP1 mutations had a personal history but no family history of breast cancer while the remaining three had a family history but no personal history of breast cancer. All five patients with BRIP1 mutations of uncertain significance had both personal and family history of breast cancer. Conclusion: The known high risk BRIP1 mutations are probably not associated with increased risk of breast cancer. However, at least some of the BRIP1 mutations of uncertain significance are likely very significant and associated with increased risk of breast cancer. This association needs to be confirmed in a larger patient population. Table 1: Carriers of BRIP1 variations of uncertain significanceSerial NumberAge at time of screeningPositive BRIP 1 mutation Personal history of breast cancerFamily history of breast cancerAncestry164BRIP1 mutation, c.817A&amp;gt;GYesYesGerman/ Irish278BRIP1 mutation, c. 2220G&amp;gt;TYesYesHolland344BRIP1 mutation, c3237T&amp;gt;GYesYesAfrican430BRIP1 mutation, c.380-17T&amp;gt;AYesYesIrish/ English/ German555BRIP1 mutation, c.139C&amp;gt;GYesYesScottish Table 2: Carriers of high risk BRIP1 mutationsSerial NumberAge at time of screeningPositive BRIP 1 mutation Personal history of breast cancerFamily history of breast cancerAncestry169BRIP1 mutation, c.2255_2256delYesNoItalian/ Hungarian263BRIP1 mutation, c548delNoYesFrench Canadian337BRIP1 mutation, c.1045G&amp;gt;CNoYesDutch460BRIP1 mutation, c.2099T&amp;gt;ANoYesUnknown Citation Format: Mukul Singal, Manasi M Godbole, Kim Povenzano, Beth Elmore, Mehul P Patel. BRCA1 interacting protein C-terminal helicase 1 (BRIP1) as a cancer susceptibility gene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-31.

Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer.

Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ 2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60-3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. SIGNIFICANCE: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

Association study between polymorphism of breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 and early-onset breast cancer in Xinjiang women of Uygur

Objective To investigate the association between single Nucleotide polymorphisms (SNPs) of breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 (BACH1) gene and susceptibility of early-onset breast cancer in Uygur women in Xinjiang. Methods Detecting and analyzing BACH1 gene exon sites by DNA direct sequencing method and Snapshot genotyping technology, in 80 early-onset breast cancer cases and 240 cases of Uygur women (≤40 years). Results In breast cancer and control groups of Uygur women, the frequencies of genotypes of rs4986764、rs4986765 and c. 587A>G of BACHI gene showed differences between breast cancer and control groups (P=0.001, P=0.011, P=0.049), rs4986764 site of TC (OR=0.086), CC (OR=0.044)and TC+ CCdominant model (OR=0.058) significantly reduced the risk of breast cancer. rs4986765 site of GG (OR=5.617), AG+ GG dominant model (OR=4.254) and c. 587A>G site of GG (OR=7.590), AG+ GG dominant model (OR=7.590) significantly increased the risk of breast cancer. In addition, the SNP-SNP interactions of dominance-genotypes (TC+ CC, AG+ GG) reduced 0.4% risk of breast cancer. Conclusion SNP of rs4986764 of BACHl gene was associated with significantly reduces risk of early-onset breast cancer in Xinjiang women of Uygur, SNP of rs4986765 and c. 587A>G were associated with significantly increases risk of breast cancer in Uygur women. Key words: Breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 gene; Single nucleotide polymorphism; Uygur; Breast cancer

BRCA1, DNA repair associated (BRCA1)- and BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1)-Mutated Ovarian Epithelial Cells Acquire a Cancer Stem Cell-Like Phenotype and Decreased Sensitivity to Cisplatin and Olaparib in Three Dimensional Spheroid Culture

BRCA1, DNA repair associated (BRCA1)- and BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1)-Mutated Ovarian Epithelial Cells Acquire a Cancer Stem Cell-Like Phenotype and Decreased Sensitivity to Cisplatin and Olaparib in Three Dimensional Spheroid Culture

Germline genetic variants in men with prostate cancer and one or more additional cancers.

Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of the disease. The aim of the current study was to describe the prevalence of pathogenic germline variants in cancer-predisposing genes in men with prostate cancer and at least 1 additional primary cancer. Using a multigene panel, the authors sequenced germline DNA from 102 men with prostate cancer and at least 1 additional primary cancer who also met ≥1 of the following criteria: 1) age ≤55 years at the time of diagnosis of the first malignancy; 2) rare tumor type or atypical presentation of a common tumor; and/or 3) ≥3 primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine whether the patient met established criteria for testing for a hereditary cancer syndrome. Sequencing identified approximately 3500 variants. Nine protein-truncating deleterious mutations were found across 6 genes, including BRCA2, ataxia telangiectasia mutated (ATM), mutL homolog 1 (MLH1), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), partner and localizer of BRCA2 (PALB2), and fibroblast growth factor receptor 3 (FGFR3). Likely pathogenic missense variants were identified in checkpoint kinase 2 (CHEK2) and homeobox protein Hox-B13 (HOXB13). In total, 11 of 102 patients (10.8%) were found to have pathogenic or likely pathogenic mutations in cancer-predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. Men with prostate cancer and at least 1 additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer-predisposing gene that may impact cancer prognosis and treatment, but the majority do not meet current criteria for clinical genetic testing. Cancer 2017;123:3925-32. © 2017 American Cancer Society.

Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair.

Unraveling the molecular mechanisms that regulate the biology of metastasis-competent circulating tumor cells (CTCs) is urgently needed to understand metastasis formation and tumor relapse. Our group previously established the first cell line (CTC-MCC-41) derived from metastasis-competent CTCs of a patient with colon cancer. In this study, we analyzed the transcriptome of CTC-MCC-41 cells using Human Genome U133 Plus 2.0 microarrays with the aim of unraveling the molecular basis of their special features (stem cell properties and ability to initiate and support metastasis formation). Comparison of the transcriptome data of metastasis-competent CTC-MCC-41 cells and of HT-29 cells (derived from a primary colon cancer) highlights the differential expression of genes that regulate energy metabolism [peroxisome proliferator-activated receptor γ coactivator 1A (PPARGC1A), peroxisome proliferator-activated receptor γ coactivator 1B (PPARGC1B), fatty acid binding protein 1 (FABP1), aldehyde dehydrogenase 3 family member A1 (ALDH3A1)], DNA repair [BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM)], and stemness [glutaminase 2 (GLS2), cystathionine-beta-synthase (CBS), and cystathionine gamma-lyase (CTH)]. The differential expression of 20 genes was validated by quantitative reverse transcription PCR. This study gives a comprehensive outlook on the molecular events involved in colon cancer progression and provides potential CTC biomarkers that may help develop new therapies to specifically target CTCs with stem cell properties that cause metastases and tumor relapse in patients with colon cancer.

Inactivation of the Tumor Suppressor BRCA1 Interacting Protein C-terminal Helicase 1 (BRIP1) Gene Confers Increased Susceptibility to Platinum Antineoplastic Agents and Augments the Synergistic Response to Poly (ADP-ribose) Polymerase (PARP) Inhibition in Ovarian Epithelial Cells

Objectives: Inactivating mutations of the tumor suppressor gene, BRIP1, are frequently identified by genetic testing. Here, we characterize a deleterious germline mutation of BRIP1 and assess response to platinum-induced DNA damage and PARP inhibition.

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

BackgroundBRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group...

BRCA1-mediated repression of mutagenic end-joining of DNA double-strand breaks requires complex formation with BACH1

BACH1 (BRCA1-associated C-terminal helicase 1), the product of the BRIP1 {BRCA1 [breast cancer 1, early onset]-interacting protein C-terminal helicase 1; also known as FANCJ [FA-J (Fanconi anaemia group J) protein]} gene mutated in Fanconi anaemia patients from complementation group J, has been implicated in DNA repair and damage signalling. BACH1 exerts DNA helicase activities and physically interacts with BRCA1 and MLH1 (mutL homologue 1), which differentially control DNA DSB (double-strand break) repair processes. The present study shows that BACH1 plays a role in both HR (homologous recombination) and MMEJ (microhomology-mediated non-homologous end-joining) and reveals discrete mechanisms underlying modulation of these pathways. Our results indicate that BACH1 stimulates HR, which depends on the integrity of the helicase domain. Disruption of the BRCA1-BACH1 complex through mutation of BACH1 compromised errorfree NHEJ (non-homologous end-joining) and accelerated error-prone MMEJ. Conversely, molecular changes in BACH1 abrogating MLH1 binding interfered neither with HR nor with MMEJ. Importantly, MMEJ is a mutagenic DSB repair pathway, which is derepressed in hereditary breast and ovarian carcinomas. Since BRCA1 and BACH1 mutations targeting the BRCA1-BACH1 interaction have been associated with breast cancer susceptibility, the results of the present study thus provide evidence for a novel role of BACH1 in tumour suppression.

BRCA Gene Structure and Function in Tumor Suppression

Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.