1/10/2024 0 Comments Susan rosenbergWe are investigating whether any of the human homologues function via the E. coli RecQ plays the opposite role, and thus exemplifies a second paradigm for the in vivo function of RecQ-family proteins. One of the human, the yeast and fly RecQ homologues, appear to play one specific role in genetic recombination in cells. coli RecQ is a close relative of five human proteins, mutations in at least three of which cause genome instability underlying cancer-predisposition syndromes: Bloom, Werner, and Rothmund-Thomson. Genomic instability including mutagenesis and chromosome rearrangement is a hallmark of cancer, yet the genomic caretaker proteins that prevent and sometimes cause instability are highly conserved and similar in all organisms. We discovered that spontaneous DNA double-strand breaks are rarer and more dangerous to genomes than predicted, and that bacteria with DNA damage undergo a senescence-like state, analogous to that in human cells.įrom Bacteria to Humans: Genomic-Caretaker Proteins and Cancer. Spontaneous DNA damage is thought to be the main culprit underlying genetic and genomic instability in all living cells. With this direct, sensitive technology we are identifying the amounts, kinds, and sources of spontaneous DNA damage in single living cells. coli cells that fluoresce green when their DNA is damaged, and are using flow cytometry to quantify and recover green cells with spontaneous DNA damage. We are examining the mechanism by which these mutations form. We are interested in molecular mechanisms that drive evolution.ĪNTIBIOTIC-RESISTANCE MUTATION: Some mutations that confer antibiotic-resistance form by a mechanism with similarities to recombination-dependent stress-induced mutagenesis described above. Stress-induced mutation mechanisms may provide important models for genome instability underlying some cancers and genetic diseases, resistance to chemotherapeutic and antibiotic drugs, pathogenicity of microbes, and many other important evolutionary processes. are stressed, potentially accelerating evolution then. The stress responses increase mutagenesis specifically when cells are maladapted to their environments, i.e. We discovered that the normally high-fidelity mechanism of DNA double-strand-break repair is switched to a mutagenic version of that mechanism, using a special error-prone DNA polymerase, specifically when cells are stressed, under the control of two cellular stress responses. coli using a variety of genetic, molecular, genomic, and whole-genome-sequencing approaches. We are elucidating molecular mechanisms by which these mutations form in E. The stress-induced mutations occur during growth-limiting stress, and can include adaptive mutations that allow growth in the otherwise growth-limiting environment. The discovery of stress-induced mutagenesis has changed ideas about mutation and evolution and revealed mutagenic programs that differ from standard spontaneous mutagenesis in rapidly proliferating cells. STRESS-INDUCED MUTAGENESIS: For 50 years the world believed that mutations occur at random. Genome Instability in Evolution, Antibiotic Resistance, and Cancer
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