We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. Anderson Cancer Center, Houston, TX, United StatesĪll tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. 5Department of Cancer Biology, University of Texas M.D.4Laboratory of DNA Replication and Recombination, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.Anderson Cancer Center, Houston, TX, United States 2Department of Molecular and Cellular Oncology, University of Texas M.D.1Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.Tsutakawa 1 †, Albino Bacolla 2 †, Panagiotis Katsonis 3 †, Amer Bralić 4, Samir M.
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