Genetic instability is a primary cellular event leading to cancers, tumor progression, and resistance to chemotherapeutic drugs. Chromosomal changes involved include somatic recombination between homologous chromosomes, promoting loss of heterozygosity, translocations between non-homologous chromosomes, gene amplification, and other DNA rearrangements in addition to mutation. These various forms of genetic instability are provoked by DNA repair events. Many of the human proteins implicated in genetic instability have homologs in eubacteria which appear to function similarly, many of which participate in DNA repair including repair of double-strand breaks (DSBs) and single-strand gaps. Agents that cause the lesions that require repair are primary carcinogens, and human genetic diseases in which homologs of the bacterial repair proteins are altered display cancer-proneness. Although genetic rearrangements and DNA replication have been thought of as separate events, and have been studied separately, many lines of recent evidence from several organisms now imply a profound connection--the promotion of DNA replication by double-strand DNA break-repair (DSBR). In only one cellular (non-viral) system has this connection been firmly and directly demonstrated: DSBR in E. coli occurs roughly half the time as a replication-promoting event, and the other half via recombination without replication. In this proposal the molecular mechanism of DSBR in the E. coli model system is investigated with the goals of elucidating structures of DNA intermediates in and products of the process, identifying all of the relevant proteins involved, and understanding control of replicative versus non-replicative mechanisms. This information will be related to genetic instability in cancer, and, in some cases, the human orthologs of E. coli repair proteins will also be examined. Because direct physical analysis of DNA, as well as sophisticated genetic tools are available in this model system, the level of detail of molecular mechanism to be obtained is unparalleled in other organisms. Because the proteins so far identified are homologous with human cancer proteins (e.g. Blm, Wrn, hRad51 which functions with Brca proteins in DSBR), and their functions are conserved, the information is directly applicable to the mechanisms of genetic instability that cause, promote, and make drug-resistant, human cancers.
| Rosenberg, Susan M; Queitsch, Christine (2014) Medicine. Combating evolution to fight disease. Science 343:1088-9 |
| Hamilton, Holly M; Wilson, Ray; Blythe, Martin et al. (2013) Thymineless death is inhibited by CsrA in Escherichia coli lacking the SOS response. DNA Repair (Amst) 12:993-9 |
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| Frisch, Ryan L; Rosenberg, Susan M (2011) Microbiology. Antibiotic resistance, not shaken or stirred. Science 333:1713-4 |
| Fonville, Natalie C; Bates, David; Hastings, P J et al. (2010) Role of RecA and the SOS response in thymineless death in Escherichia coli. PLoS Genet 6:e1000865 |
| Fonville, Natalie C; Blankschien, Matthew D; Magner, Daniel B et al. (2010) RecQ-dependent death-by-recombination in cells lacking RecG and UvrD. DNA Repair (Amst) 9:403-13 |
| Galhardo, Rodrigo S; Rosenberg, Susan M (2009) Extreme genome repair. Cell 136:998-1000 |
| Hastings, P J; Lupski, James R; Rosenberg, Susan M et al. (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551-64 |
| Pennington, Jeanine M; Rosenberg, Susan M (2007) Spontaneous DNA breakage in single living Escherichia coli cells. Nat Genet 39:797-802 |
| Magner, Daniel B; Blankschien, Matthew D; Lee, Jennifer A et al. (2007) RecQ promotes toxic recombination in cells lacking recombination intermediate-removal proteins. Mol Cell 26:273-86 |
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