FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2075260752> ?p ?o ?g. }

• W2075260752 abstract "Inherited germline mutations in a single copy of the BRCA2 tumor suppressor predispose individuals to breast, ovarian, pancreatic and other cancers. BRCA2 exerts its tumor suppressive function in the cell nucleus through its role in the repair of DNA breaks by homologous recombination, where it controls the accumulation of the RAD51 recombinase enzyme at sites of DNA breakage. Cancer associated in-frame point mutations in BRCA2 have been shown to result in cytoplasmic localization of the protein, but the mechanism underlying this is unclear.Here, we identify an unrecognized mechanism controlling the nuclear localization of BRCA2 and its cargo RAD51, which is disrupted by the common cancer-associated mis-sense mutation BRCA2 D2723H . A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mis-localization of mutant BRCA2 inhibits the nuclear retention of RAD51, by exposing a similar NES in RAD51 that is usually obscured by the BRCA2-RAD51 interaction. We demonstrate the functionality of these export sequences by cellular localization assays and in vitro binding analyses to the exportin CRM1.We note two key implications of our work. Firstly, CRM1 mediated nuclear export is relevant to the localization of tumor suppressors such as p53 and BRCA1. However, this is the first report to our knowledge, of a ‘cascade’ of NES-masking interactions mediating nuclear localization for a tumor suppressor pathway. Our findings suggest the exploration of analogous mechanisms in other cancer-relevant cellular networks. Secondly, we also note that BRCA2D2723H decreases RAD51 nuclear retention even when wildtype BRCA2 is present. This is consistent with a transdominant effect for at least a fraction of the heterozygous disease-associated mutations noted in BRCA2 . We find an increase in endogenous DNA damage in cells heterozygous for the D2723H mutation, suggesting that BRCA2 D2723H heterozygosity causes a cumulative effect on genome stability in patients, which acts over years to promote carcinogenesis. Transdominance may also explain the paradox of tumorigenesis occurring in certain cases without a somatic second hit to BRCA2.Together, our results link the nucleo-cytoplasmic translocation of the BRCA2 tumor suppressor to the cellular mechanisms of disease following its germline inactivation.Citation Format: Anand D. Jeyasekharan, Yang Liu, Hiroyoshi Hattori, Venkat Pisupati, Eeson Rajendra, Asta Bjork Jonsdottir, Miyoung Lee, Elayanambi Sundaramoorthy, Simon Schlachter, Ashok Venkitaraman. A cascade of masked nuclear export signals regulates the BRCA2 tumor suppressor pathway. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A24." @default.
• W2075260752 created "2016-06-24" @default.
• W2075260752 creator A5008789298 @default.
• W2075260752 creator A5021482443 @default.
• W2075260752 creator A5023363049 @default.
• W2075260752 creator A5039327442 @default.
• W2075260752 creator A5057362527 @default.
• W2075260752 creator A5060928128 @default.
• W2075260752 creator A5074970937 @default.
• W2075260752 creator A5081542911 @default.
• W2075260752 creator A5086913774 @default.
• W2075260752 creator A5090674878 @default.
• W2075260752 date "2013-10-01" @default.
• W2075260752 modified "2023-09-27" @default.
• W2075260752 title "Abstract A24: A cascade of masked nuclear export signals regulates the BRCA2 tumor suppressor pathway" @default.
• W2075260752 doi "https://doi.org/10.1158/1538-7445.fbcr13-a24" @default.
• W2075260752 hasPublicationYear "2013" @default.
• W2075260752 type Work @default.
• W2075260752 sameAs 2075260752 @default.
• W2075260752 citedByCount "0" @default.
• W2075260752 crossrefType "proceedings-article" @default.
• W2075260752 hasAuthorship W2075260752A5008789298 @default.
• W2075260752 hasAuthorship W2075260752A5021482443 @default.
• W2075260752 hasAuthorship W2075260752A5023363049 @default.
• W2075260752 hasAuthorship W2075260752A5039327442 @default.
• W2075260752 hasAuthorship W2075260752A5057362527 @default.
• W2075260752 hasAuthorship W2075260752A5060928128 @default.
• W2075260752 hasAuthorship W2075260752A5074970937 @default.
• W2075260752 hasAuthorship W2075260752A5081542911 @default.
• W2075260752 hasAuthorship W2075260752A5086913774 @default.
• W2075260752 hasAuthorship W2075260752A5090674878 @default.
• W2075260752 hasConcept C102744134 @default.
• W2075260752 hasConcept C104317684 @default.
• W2075260752 hasConcept C121608353 @default.
• W2075260752 hasConcept C134935766 @default.
• W2075260752 hasConcept C13514818 @default.
• W2075260752 hasConcept C179185449 @default.
• W2075260752 hasConcept C190062978 @default.
• W2075260752 hasConcept C2779012473 @default.
• W2075260752 hasConcept C2780114586 @default.
• W2075260752 hasConcept C2909462720 @default.
• W2075260752 hasConcept C49805395 @default.
• W2075260752 hasConcept C501734568 @default.
• W2075260752 hasConcept C502942594 @default.
• W2075260752 hasConcept C54355233 @default.
• W2075260752 hasConcept C54757728 @default.
• W2075260752 hasConcept C552990157 @default.
• W2075260752 hasConcept C86803240 @default.
• W2075260752 hasConcept C95444343 @default.
• W2075260752 hasConceptScore W2075260752C102744134 @default.
• W2075260752 hasConceptScore W2075260752C104317684 @default.
• W2075260752 hasConceptScore W2075260752C121608353 @default.
• W2075260752 hasConceptScore W2075260752C134935766 @default.
• W2075260752 hasConceptScore W2075260752C13514818 @default.
• W2075260752 hasConceptScore W2075260752C179185449 @default.
• W2075260752 hasConceptScore W2075260752C190062978 @default.
• W2075260752 hasConceptScore W2075260752C2779012473 @default.
• W2075260752 hasConceptScore W2075260752C2780114586 @default.
• W2075260752 hasConceptScore W2075260752C2909462720 @default.
• W2075260752 hasConceptScore W2075260752C49805395 @default.
• W2075260752 hasConceptScore W2075260752C501734568 @default.
• W2075260752 hasConceptScore W2075260752C502942594 @default.
• W2075260752 hasConceptScore W2075260752C54355233 @default.
• W2075260752 hasConceptScore W2075260752C54757728 @default.
• W2075260752 hasConceptScore W2075260752C552990157 @default.
• W2075260752 hasConceptScore W2075260752C86803240 @default.
• W2075260752 hasConceptScore W2075260752C95444343 @default.
• W2075260752 hasLocation W20752607521 @default.
• W2075260752 hasOpenAccess W2075260752 @default.
• W2075260752 hasPrimaryLocation W20752607521 @default.
• W2075260752 hasRelatedWork W1599522161 @default.
• W2075260752 hasRelatedWork W1980085643 @default.
• W2075260752 hasRelatedWork W1980110830 @default.
• W2075260752 hasRelatedWork W1992738021 @default.
• W2075260752 hasRelatedWork W2002931411 @default.
• W2075260752 hasRelatedWork W2019602804 @default.
• W2075260752 hasRelatedWork W2057620850 @default.
• W2075260752 hasRelatedWork W2072264214 @default.
• W2075260752 hasRelatedWork W2090651325 @default.
• W2075260752 hasRelatedWork W2092726292 @default.
• W2075260752 hasRelatedWork W2100747540 @default.
• W2075260752 hasRelatedWork W2102976776 @default.
• W2075260752 hasRelatedWork W2126668502 @default.
• W2075260752 hasRelatedWork W2312397099 @default.
• W2075260752 hasRelatedWork W2715937868 @default.
• W2075260752 hasRelatedWork W2739416909 @default.
• W2075260752 hasRelatedWork W2966898099 @default.
• W2075260752 hasRelatedWork W2990904963 @default.
• W2075260752 hasRelatedWork W3012015064 @default.
• W2075260752 hasRelatedWork W874049513 @default.
• W2075260752 isParatext "false" @default.
• W2075260752 isRetracted "false" @default.
• W2075260752 magId "2075260752" @default.
• W2075260752 workType "article" @default.