""""""""Adaptive """""""" mutations occur in stationary cell populations, only after the cells are exposed to selection for the mutation, and, previously, had been found only in genes whose functions were selected. Their discovery challenged established ideas about the mechanisms of mutation and evolution. In one system, reversion of a lac frameshift mutation in E. coli, aspects of the molecular mechanism are becoming apparent, and indicate a novel mutagenic route involving DNA double strand breaks, homologous recombination, DNA synthesis with polymerase errors, and depression of post-synthesis mismatch repair at the protein level. This mechanism is general to all replicons in the cell, not directed to the lac gene in a Lamarckian manner, and occurs in a hypermutable subpopulation of the cells exposed to the selection. This proposal is aimed at providing a complete description of the molecular mechanism of the recombination dependent adaptive mutation in this system, and defining the generality of this mechanism elsewhere. Understanding the molecular mechanism will provide a valuable new model for mutagenesis in non-dividing and slowly growing cells. This model might apply to mutagenesis in the origins of some cancers and genetic diseases, evolution of drug resistance in tumors and pathogenic bacteria, and many other systems previously assumed to follow the rules of Luria/Delbruck growth-dependent mutation.
| Fitzgerald, Devon M; Hastings, P J; Rosenberg, Susan M (2017) Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance. Annu Rev Cancer Biol 1:119-140 |
| Dohrmann, Paul R; Correa, Raul; Frisch, Ryan L et al. (2016) The DNA polymerase III holoenzyme contains ? and is not a trimeric polymerase. Nucleic Acids Res 44:1285-97 |
| Nehring, Ralf B; Gu, Franklin; Lin, Hsin-Yu et al. (2016) An ultra-dense library resource for rapid deconvolution of mutations that cause phenotypes in Escherichia coli. Nucleic Acids Res 44:e41 |
| Barreto, Brittany; Rogers, Elizabeth; Xia, Jun et al. (2016) The Small RNA GcvB Promotes Mutagenic Break Repair by Opposing the Membrane Stress Response. J Bacteriol 198:3296-3308 |
| Moore, Jessica M; Magnan, David; Mojica, Ana K et al. (2015) Roles of Nucleoid-Associated Proteins in Stress-Induced Mutagenic Break Repair in Starving Escherichia coli. Genetics 201:1349-62 |
| Gibson, Janet L; Lombardo, Mary-Jane; Aponyi, Ildiko et al. (2015) Atypical Role for PhoU in Mutagenic Break Repair under Stress in Escherichia coli. PLoS One 10:e0123315 |
| Bos, Julia; Zhang, Qiucen; Vyawahare, Saurabh et al. (2015) Emergence of antibiotic resistance from multinucleated bacterial filaments. Proc Natl Acad Sci U S A 112:178-83 |
| Rosenberg, Susan M; Queitsch, Christine (2014) Medicine. Combating evolution to fight disease. Science 343:1088-9 |
| Wimberly, Hallie; Shee, Chandan; Thornton, P C et al. (2013) R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli. Nat Commun 4:2115 |
| Walker, Sara Imari; Callahan, Benjamin J; Arya, Gaurav et al. (2013) Evolutionary dynamics and information hierarchies in biological systems. Ann N Y Acad Sci 1305:1-17 |
Showing the most recent 10 out of 60 publications
