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Previously, we quantified the effects of missense mutations on the thermodynamic stability of the BRCT domains, and we showed that many are so destabilizing that the folded functional state is drastically depopulated at physiological temperature. In the present study, we ask whether and how reduced thermodynamic stability of the isolated BRCT mutants translates into loss of function of the full-length protein in the cell. We assessed the effects of missense mutants on different stages of BRCA1-mediated DNA repair by homologous recombination using chicken lymphoblastoid DT40 cells as a model system. We found that all of the mutations, regardless of how profound their destabilizing effects, retained some DNA repair activity and thereby partially rescued the chicken BRCA1 knockout. By contrast, the mutation R1699L, which disrupts the binding of phosphorylated proteins (but which is not destabilizing), was completely inactive. It is likely that both protein context (location of the BRCT domains at the C-terminus of the large BRCA1 protein) and cellular environment (binding partners, molecular chaperones) buffer these destabilizing effects such that at least some mutant protein is able to adopt the folded functional state.<\/jats:p>","DOI":"10.1042\/bj20141077","type":"journal-article","created":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T16:17:59Z","timestamp":1425658679000},"page":"613-624","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Protein stability versus function: effects of destabilizing missense mutations on <i>BRCA1<\/i> DNA repair activity"],"prefix":"10.1042","volume":"466","author":[{"given":"David\u00a0C.A.","family":"Gaboriau","sequence":"first","affiliation":[{"name":"Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland"},{"name":"Medical Research Council (MRC) Cancer Cell Unit, Hutchison\/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela\u00a0J.E.","family":"Rowling","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Cancer Cell Unit, Hutchison\/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, U.K."},{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciaran\u00a0G.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura\u00a0S.","family":"Itzhaki","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Cancer Cell Unit, Hutchison\/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, U.K."},{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2015,3,6]]},"reference":[{"key":"2021112216163760700_B1","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/S1097-2765(00)80202-6","article-title":"Brca1 controls homology-directed DNA repair","volume":"4","author":"Moynahan","year":"1999","journal-title":"Mol. 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