Breast Cancer-Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions

Laboratory of Cancer Genetics, Department of Clinical Genetics, Institute of Clinical Medicine and Biocenter Oulu, University of Oulu, Oulu University Hospital, Aapistie 5A, FI-90220 Oulu, Finland.
Science translational medicine (Impact Factor: 15.84). 02/2012; 4(122):122ra23. DOI: 10.1126/scitranslmed.3003223
Source: PubMed


Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c.1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.

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Available from: Szilvia Solyom, Aug 22, 2014
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    • "Failure to achieve nuclear retention adversely affects the G2/M checkpoint and homology-directed DNA repair, which reduces nuclear retention of ABRAXAS-interacting partners to DSB site (Solyom et al., 2012). Moreover, expression of the Arg361Gln variant causes hypersensitivity to ionizing radiation and reduces BRCA1 localization at the sites of DNA damage (Solyom et al., 2012). ABRAXAS, as a newly emerging susceptibility gene to cancer predisposition, opens the vast perspective of studying the role and impact of genetic alteration in disease progression. "
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    ABSTRACT: ABRAXAS is an integral member of BRCA1-complex, which helps in its recruitment to the DNA damage site. It interacts with BRCA1 via its C-terminal phospho-peptide binding motif while the N-terminal associates with RAP80, and thereby recruits the BRCA1-complex at the site of DNA damage. Nonetheless, how ABRAXAS helps in the structural integrity of BRCA1-complex, and its DNA repair mechanism remains elusive. To elucidate the role of ABRAXAS in the DNA repair process, we characterized the ABRAXAS wild type and Arg361Gln mutant using in silico and in vitro approach. It has been observed that ABRAXAS Arg361Gln mutant is responsible for defective nuclear localization of BRCA1-complex, and hence important for DNA repair function. We found conformational changes in ABRAXAS mutant, which impaired binding to RAP80 and further disturb BRCA1-complex localization. The results presented in this paper will help to understand the cause of BRCA1 mislocalization, and various DNA repair defects that occur due to substitution. Comparative study of ABRAXAS wild type and mutant will provide helpful perspective for inhibitor designing that can potentially recompense the deleterious effect(s) of Arg361Gln mutation, and have therapeutic application.
    Full-text · Article · Aug 2014 · Journal of biomolecular Structure & Dynamics
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    • "A new candidate that has become evident through the present analysis is the Abraxas gene [68] that has two synonymous terms, FAM175A and CCDC98. Abraxas, which has recently been reported in breast cancer owing to its association with BRCA1 BRCT (BRCA1 C-terminal) repeats motif [69], links BRCA1 to a protein complex dedicated to ubiquitin chain recognition and hydrolysis at DNA double strand breaks, and is thus involved in BRCA1-dependent DNA damage response [70,71]. "
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    ABSTRACT: Background Genomic, proteomic and high-throughput gene expression data, when integrated, can be used to map the interaction networks between genes and proteins. Different approaches have been used to analyze these networks, especially in cancer, where mutations in biologically related genes that encode mutually interacting proteins are believed to be involved. This system of integrated networks as a whole exhibits emergent biological properties that are not obvious at the individual network level. We analyze the system in terms of modules, namely a set of densely interconnected nodes that can be further divided into submodules that are expected to participate in multiple biological activities in coordinated manner. Results In the present work we construct two layers of the breast cancer network: the gene layer, where the correlation network of breast cancer genes is analyzed to identify gene modules, and the protein layer, where each gene module is extended to map out the network of expressed proteins and their interactions in order to identify submodules. Each module and its associated submodules are analyzed to test the robustness of their topological distribution. The constituent biological phenomena are explored through the use of the Gene Ontology. We thus construct a “network of networks”, and demonstrate that both the gene and protein interaction networks are modular in nature. By focusing on the ontological classification, we are able to determine the entire GO profiles that are distributed at different levels of hierarchy. Within each submodule most of the proteins are biologically correlated, and participate in groups of distinct biological activities. Conclusions The present approach is an effective method for discovering coherent gene modules and protein submodules. We show that this also provides a means of determining biological pathways (both novel and as well those that have been reported previously) that are related, in the present instance, to breast cancer. Similar strategies are likely to be useful in the analysis of other diseases as well.
    Full-text · Article · Jul 2014 · BMC Systems Biology
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    • "Additionally, RAP80, Abraxas, and RAD51AP1 have functional interactions with PALB2[62,92]. Among these, RAP80 and Abraxas are also tumor suppressors[4,160]. Thus, PALB2 appears to function in a network of tumor suppressors. "
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    ABSTRACT: PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
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