Host Cell Reactivation and Transcriptional Activation of Carboplatin-Modified BRCA1

The breast cancer susceptibility gene 1 ( BRCA1) has been shown to maintain genomic stability through multiple functions in the regulation of DNA damage repair and transcription. Its translated BRCT (BRCA1 C-terminal domain) acts as a strong transcriptional activator. BRCA1 damaged by carboplatin treatment may lead to a loss of such functions. To address the possibility of the BRCA1 gene as a therapeutic target for carboplatin, we investigated the functional consequences of the 3′-terminal region of human BRCA1 following in vitro platination with carboplatin. A reduction in cellular BRCA1 repair of carboplatin-treated plasmid DNA, using a host cell reactivation assay, was dependent on the platination levels on the reporter gene. The transcriptional transactivation activity of the drug-modified BRCA1, assessed using a one-hybrid GAL4 transcriptional assay, was inversely proportional to the carboplatin doses. The data emphasized the potential of the BRCA1 gene to be a target for carboplatin treatment.

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Absence of High Penetrance Genes Mutations in Familial Breast Cancer in Mizo-Mongloid Population, Northeast India

10.21203/rs.3.rs-21839/v1 ◽

2020 ◽

Author(s):

Doris Zodinpuii ◽

Bawitlung Zothankima ◽

Jeremy Lalrinsanga Pautu ◽

Doris Lallawmzuali ◽

Ashok Kumar Varma ◽

...

Keyword(s):

Breast Cancer ◽

Familial Breast Cancer ◽

Cancer Susceptibility ◽

Mutation Screening ◽

Susceptibility Gene ◽

Gene Mutations ◽

Brca1 Gene ◽

Breast Cancer Susceptibility ◽

Breast Cancer Susceptibility Gene ◽

Cancer Susceptibility Genes

Abstract Background: Breast cancer is the most prevalent cancer and leading cause of death among women globally. The present study focuses on screening germline mutations of breast cancer susceptibility genes among the unexplored Mizo breast cancers of culturally and historically homogenous population, living a unique life style habits in terms of diet and tobacco usage. Methods Mutation screening was performed using Sanger sequencing in complete coding region of BRCA1 and frequently mutated exons of TP53, PTEN, CDH1, CHEK2 and XRCC2. Several online mutation prediction tools and databases were used to check the pathogenicity of the polymorphisms observed. Results: We observed eight polymorphisms in total, in which, one variants p.P1544P in BRCA1 gene was found to be novel. No variants were found to have a potential impact on protein since all the polymorphisms are of silent substitutions. No genetic alteration was observed in the studied exons of each of TP53, PTEN, CDH1, CHEK2 and XRCC2. Conclusion: To our knowledge, the present study focusing on familial breast cancer is the first time to analyzed the prevalence of breast cancer susceptibility gene mutations using direct sequencing in Mizo population. Even though, we do not find significant amino acid change, our results suggest the need for further evaluation of broader panel genes and a challenge to screen larger sample size to establish the contribution of these gene mutations in this population.

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DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data

Biochemical Society Transactions ◽

10.1042/bst0330715 ◽

2005 ◽

Vol 33 (4) ◽

pp. 715-717 ◽

Cited By ~ 5

Author(s):

T. Hay ◽

A.R. Clarke

Keyword(s):

Cancer Susceptibility ◽

Susceptibility Gene ◽

Short Review ◽

Breast Cancer Susceptibility ◽

Breast Cancer Susceptibility Gene ◽

Functional Protein ◽

Increased Sensitivity ◽

Cancer Susceptibility Gene

Since the discovery of the tumour suppressor BRCA2 (encoded by breast-cancer susceptibility gene 2), cells lacking the fully functional protein have consistently been found to show increased sensitivity to a variety of DNA-damaging agents, particularly those that cross-link DNA. In this short review, we will bring together these findings and discuss them in the light of our recent in vivo data in the mouse small intestine, which suggests that deletion of cells lacking Brca2 is necessary to avoid the development of potentially tumorigenic clones in this tissue, a system that may be less effective in the mammary glands of humans with germline mutations in BRCA2.

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Characterization of the interaction between the human DNA topoisomerase IIβ-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein

Biochemical Journal ◽

10.1042/bj20070872 ◽

2007 ◽

Vol 409 (1) ◽

pp. 169-177 ◽

Cited By ~ 23

Author(s):

Uta Schmidt ◽

Yvonne Wollmann ◽

Claudia Franke ◽

Frank Grosse ◽

Hans-Peter Saluz ◽

...

Keyword(s):

Cell Division ◽

Dna Replication ◽

Transcriptional Activation ◽

Glutathione Transferase ◽

Cancer Susceptibility ◽

Binding Protein ◽

Susceptibility Gene ◽

Cell Division Cycle ◽

Breast Cancer Susceptibility Gene

TopBP1 (topoisomerase IIβ-binding protein 1) is a BRCT [BRCA1 (breast-cancer susceptibility gene 1) C-terminal]-domain-rich protein that is structurally and functionally conserved throughout eukaryotic organisms. It is required for the initiation of DNA replication and for DNA repair and DNA damage signalling. Experiments with fission yeast and Xenopus revealed that the TopBP1 homologues of these organisms are required for chromatin loading of the replication protein Cdc45 (cell division cycle 45). To improve our understanding of the physiological functions of human TopBP1, we investigated the interplay between human TopBP1 and Cdc45 proteins in synchronized HeLa-S3 cells. Using GST (glutathione transferase) pull-down and co-immunoprecipitation techniques, we showed a direct interaction between TopBP1 and Cdc45 in vitro and in vivo. The use of deletion mutants in GST pull-down assays identified the first and second as well as the sixth BRCT domains of TopBP1 to be responsible for the functional interaction with Cdc45. Moreover, the interaction between Cdc45 and the first and second BRCT domains of TopBP1 inhibited their transcriptional activation both in yeast and mammalian one-hybrid systems. Both proteins interacted exclusively at the G1/S boundary of cell cycle; only weak interaction could be found at the G2/M boundary. The overexpression of the sixth BRCT domain led to diminished loading of Cdc45 on to chromatin. These results suggest that human TopBP1 is involved in the formation of the initiation complex of replication in human cells and is required for the recruitment of Cdc45 to origins of DNA replication.

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Long Non-Coding RNA Neighbor of BRCA1 Gene 2: A Crucial Regulator in Cancer Biology

Frontiers in Oncology ◽

10.3389/fonc.2021.783526 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ting Wang ◽

Zhaosheng Li ◽

Liujia Yan ◽

Feng Yan ◽

Han Shen ◽

...

Keyword(s):

Cancer Biology ◽

Molecular Mechanisms ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Brca1 Gene ◽

Breast Cancer Susceptibility ◽

Suppressor Gene ◽

Breast Cancer Susceptibility Gene ◽

Non Coding Rna ◽

Cancer Intervention

Long non-coding RNAs (lncRNAs) are involved in fundamental biochemical and cellular processes. The neighbor of BRCA1 gene 2 (NBR2) is a long intergenic non-coding RNA (lincRNA) whose gene locus is adjacent to the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1). In human cancers, NBR2 expression is dysregulated and correlates with clinical outcomes. Moreover, NBR2 is crucial for glucose metabolism and affects the proliferation, survival, metastasis, and therapeutic resistance in different types of cancer. Here, we review the precise molecular mechanisms underlying NBR2-induced changes in cancer. In addition, the potential application of NBR2 in the diagnosis and treatment of cancer is also discussed, as well as the challenges of exploiting NBR2 for cancer intervention.

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