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Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.
Pubmed ID: 29334356 RIS Download
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Commercial antibody vendor which supplies antibodies and other products to life science researchers.
View all literature mentionsCommercial instrument and chemical vendor. Developer and manufacturer of specialized technological products for life science research and clinical diagnostics markets.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsProject exploring the spectrum of genomic changes involved in more than 20 types of human cancer that provides a platform for researchers to search, download, and analyze data sets generated. As a pilot project it confirmed that an atlas of changes could be created for specific cancer types. It also showed that a national network of research and technology teams working on distinct but related projects could pool the results of their efforts, create an economy of scale and develop an infrastructure for making the data publicly accessible. Its success committed resources to collect and characterize more than 20 additional tumor types. Components of the TCGA Research Network: * Biospecimen Core Resource (BCR); Tissue samples are carefully cataloged, processed, checked for quality and stored, complete with important medical information about the patient. * Genome Characterization Centers (GCCs); Several technologies will be used to analyze genomic changes involved in cancer. The genomic changes that are identified will be further studied by the Genome Sequencing Centers. * Genome Sequencing Centers (GSCs); High-throughput Genome Sequencing Centers will identify the changes in DNA sequences that are associated with specific types of cancer. * Proteome Characterization Centers (PCCs); The centers, a component of NCI's Clinical Proteomic Tumor Analysis Consortium, will ascertain and analyze the total proteomic content of a subset of TCGA samples. * Data Coordinating Center (DCC); The information that is generated by TCGA will be centrally managed at the DCC and entered into the TCGA Data Portal and Cancer Genomics Hub as it becomes available. Centralization of data facilitates data transfer between the network and the research community, and makes data analysis more efficient. The DCC manages the TCGA Data Portal. * Cancer Genomics Hub (CGHub); Lower level sequence data will be deposited into a secure repository. This database stores cancer genome sequences and alignments. * Genome Data Analysis Centers (GDACs) - Immense amounts of data from array and second-generation sequencing technologies must be integrated across thousands of samples. These centers will provide novel informatics tools to the entire research community to facilitate broader use of TCGA data. TCGA is actively developing a network of collaborators who are able to provide samples that are collected retrospectively (tissues that had already been collected and stored) or prospectively (tissues that will be collected in the future).
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1299 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets biotin (D5A7) Rabbit mAb
View all literature mentionsThis polyclonal targets KMT2C / MLL3
View all literature mentionsThis monoclonal targets Rad51
View all literature mentionsThis monoclonal targets Yeast (Saccharomyces cerevisiae) ORC2
View all literature mentionsThis monoclonal targets Mouse Clone BN-34
View all literature mentionsThis monoclonal targets Rad52 (F-7)
View all literature mentionsThis monoclonal targets Mre11
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis polyclonal targets DNA Polymerase theta antibody
View all literature mentionsThis polyclonal targets Ku70
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsMicroscope imaging software suite used with Nikon products. NIS-Elements includes software applications for advanced and standard research, documentation, confocal microscopy, and high-content analysis.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE, documented August 7, 2017. Software designed for objective quantification/counting of PLA signals in cells and tissue images generated from fluorescence microscopy. The nuclei are automatically detected and cytoplasm size estimated, enabling single cell statistical analysis of expression levels in tissue or cell populations.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HAP1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsThis monoclonal targets Yeast (Saccharomyces cerevisiae) ORC2
View all literature mentionsThis monoclonal targets Rad51
View all literature mentionsThis polyclonal targets KMT2C / MLL3
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE, documented August 7, 2017. Software designed for objective quantification/counting of PLA signals in cells and tissue images generated from fluorescence microscopy. The nuclei are automatically detected and cytoplasm size estimated, enabling single cell statistical analysis of expression levels in tissue or cell populations.
View all literature mentionsMicroscope imaging software suite used with Nikon products. NIS-Elements includes software applications for advanced and standard research, documentation, confocal microscopy, and high-content analysis.
View all literature mentionsThis polyclonal targets Ku70
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis polyclonal targets DNA Polymerase theta antibody
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets Rad52 (F-7)
View all literature mentionsThis monoclonal targets biotin (D5A7) Rabbit mAb
View all literature mentionsThis monoclonal targets Mouse Clone BN-34
View all literature mentionsCell line MCF-10A is a Spontaneously immortalized cell line with a species of origin Homo sapiens
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HAP1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MCF-10A is a Spontaneously immortalized cell line with a species of origin Homo sapiens
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets Mre11
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