Nucleolar exit of RNF8 and BRCA1 in response to DNA damage

Guerra-Rebollo, Marta; Mateo, Francesca; Franke, Kristin; Huen, Msy; Lopitz‐Otsoa, Fernando; Rodríguez, Manuel Sánchez; Plans, Vanessa; Thomson, Timothy M.

doi:10.1016/j.yexcr.2012.07.003

Cited by 24 publications

(17 citation statements)

References 42 publications

(65 reference statements)

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“…We have used freezing in liquid N2, followed by -20o C methanol fixation of the captured frozen sections in order to minimize translocation of antigen during fixation. Guerra–Rebollo et al [43] also found that after using methanol fixation, BRCA1 was localized in nucleoli, but after ᵧ-irradiation BRCA1 was depleted from the nucleolus, and associated with ionizing-radiation induced foci (IRIF).…”

Section: Discussionmentioning

confidence: 99%

“…The functions of BRCA1 protein are yet to be fully elucidated, however, BRCA1 protein participates in many signaling pathways involved in transcription, checkpoint control, and is recruited for the formation of DNA repair complexes in association with proteins such as Mre11-Nbs1-Rad50, and BRCA2 [45]. The data that BRCA1 is localized in the nucleolus, in addition to speckles, may explain a possible functional participation in processes of ribosomal biosynthesis, cell cycle progression, and as a reservoir for complexes formed in response to cellular stress and DNA repair [27,43]. …”

Section: Discussionmentioning

confidence: 99%

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Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Tulchin

Ornstein

Dikman

et al. 2013

Cancer Cell International

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BackgroundThe breast and ovarian cancer susceptibility gene (BRCA1) encodes a tumor suppressor. The BRCA1 protein is found primarily in cell nuclei and plays an important role in the DNA damage response and transcriptional regulation. Deficiencies in DNA repair capabilities have been associated with higher histopathological grade and worse prognosis in breast cancer.MethodsIn order to investigate the subcellular distribution of BRCA1 in tumor tissue we randomly selected 22 breast carcinomas and tested BRCA1 protein localization in frozen and contiguous formalin-fixed, paraffin embedded (FFPE) tissue, using pressure cooker antigen-retrieval and the MS110 antibody staining. To assess the impact of BRCA1 germline mutations on protein localization, we retrospectively tested 16 of the tumor specimens to determine whether they contained the common Ashkenazi Jewish founder mutations in BRCA1 (185delAG, 5382insC), and BRCA2 (6174delT). We also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC).ResultsIn FFPE tissue, with MS110 antibody staining, we frequently found reduced BRCA1 nuclear staining in breast tumor tissue compared to normal tissue, and less BRCA1 staining with higher histological grade in the tumors. However, in the frozen sections, BRCA1 antibody staining showed punctate, intra-nuclear granules in varying numbers of tumor, lactating, and normal cells. Two mutation carriers were identified and were confirmed by gene sequencing. We have also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC) and found altered sub-nuclear and nucleolar localization patterns consistent with a functional impact of the mutation on protein localization.ConclusionsThe data presented here support a role for BRCA1 in the pathogenesis of sporadic and inherited breast cancers. The use of well-characterized reagents may lead to further insights into the function of BRCA1 and possibly the further development of targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Tulchin

Ornstein

Dikman

et al. 2013

Cancer Cell International

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“…LAMR 37 may also serve to sequester the DNA damage repair proteins RNF8 (ring finger protein 8) and BRCA1 (breast cancer 1) to a waiting reserve in the nucleolus (Guerra‐Rebollo et al, ). Intriguingly, RNF8 is an E3 ubiquitin ligase, and in this context, evidence for a polyubiquitinated LAMR species was found.…”

Section: /67‐kda Laminin Receptor Functionmentioning

confidence: 99%

Looking into laminin receptor: critical discussion regarding the non‐integrin 37/67‐kDalaminin receptor/RPSAprotein

2015

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The 37/67-kDa laminin receptor (LAMR/RPSA) was originally identified as a 67-kDa binding protein for laminin, an extracellular matrix glycoprotein that provides cellular adhesion to the basement membrane. LAMR has evolutionary origins, however, as a 37-kDa RPS2 family ribosomal component. Expressed in all domains of life, RPS2 proteins have been shown to have remarkably diverse physiological roles that vary across species. Contributing to laminin binding, ribosome biogenesis, cytoskeletal organization, and nuclear functions, this protein governs critical cellular processes including growth, survival, migration, protein synthesis, development, and differentiation. Unsurprisingly given its purview, LAMR has been associated with metastatic cancer, neurodegenerative disease and developmental abnormalities. Functioning in a receptor capacity, this protein also confers susceptibility to bacterial and viral infection. LAMR is clearly a molecule of consequence in human disease, directly mediating pathological events that make it a prime target for therapeutic interventions. Despite decades of research, there are still a large number of open questions regarding the cellular biology of LAMR, the nature of its ability to bind laminin, the function of its intrinsically disordered C-terminal region and its conversion from 37 to 67 kDa. This review attempts to convey an in-depth description of the complexity surrounding this multifaceted protein across functional, structural and pathological aspects.

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“…Intriguingly, both of these proteins function within RNA metabolism pathways through their E3 ligase activity, suggesting that such an enzymatic feature might be one of the hallmarks of proteins involved in both DNA DSB repair and RNA metabolism. RNF8, an important E3 ubiquitin ligase, known for its role in DSB signaling via ubiquitination of histones surrounding DNA DSB sites, has been shown to directly interact with the RPSA ribosomal protein via its FHA domain in the nucleolus, and RNF8 silencing leads to deficient protein translation, possibly indicating a role for RNF8 in ribosome biogenesis and/or mRNA decay pathways associated with the translation machinery . Another protein with a dual role in DNA DSB repair and RNA metabolism is BRCA1, or more specifically the BRCA1/BARD1 heterodimer, the recent findings of which will be discussed below.…”

Section: Links Between the Ddr And Rna Metabolism Pathwaysmentioning

confidence: 99%

Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

2016

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Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post-transcriptional regulation of RNAs. WIREs RNA 2016, 7:604-619. doi: 10.1002/wrna.1353 For further resources related to this article, please visit the WIREs website.

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Nucleolar exit of RNF8 and BRCA1 in response to DNA damage

Cited by 24 publications

References 42 publications

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Looking into laminin receptor: critical discussion regarding the non‐integrin 37/67‐kDalaminin receptor/RPSAprotein

Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

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