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THE MECHANISM OF DAMAGE-INDUCED MUTATIONS
IN ESCHERICHIA COLI
by
Katharina Schlacher
______________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirement for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
December 2006
Copyright 2006 Katharina Schlacher
Object Description
| Title | The mechanism of damage-induced mutations in Escherichia coli |
| Author | Schlacher, Katharina |
| Author email | schlache@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular & Computational Biology |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2006-10-17 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-10-24 |
| Advisor (committee chair) | Goodman, Myron F. |
| Advisor (committee member) |
Arbeitman, Michelle N. Bau, Robert |
| Abstract | The integrity of the genome is fundamental to the survival of an organism. Escherichia coli possesses an inducible, physiological reaction to DNA damage. The SOS response, as the phenomena had come to be known, involves an upregulation of otherwise repressed genes that are engaged in DNA repair, replication and recombination. An accompanying consequence is the large increase in mutations caused by translesion DNA synthesis (TLS). TLS requires DNA polymerase V and RecA protein.; Here, the intimate relationship between these proteins is investigated. Pol V (UmuD'2C) and RecA interact by two distinct mechanisms. First, pol V binds RecA in the absence of DNA and ATP and second, through its UmuD' subunit, requiring DNA and ATP. These binding interactions do not involve multiple RecA molecules in the form of a RecA filament, which is the active species of the protein during other cellular events. Also, a RecA filament is not required for TLS per se, but a 3' proximal filament end suffices. In fact, RecA filaments obstruct replication. A model is presented that reflects the indispensability of RecA protein during SOS mutagenesis and defines RecA to be an integral subunit of a "minimal mutasome" complex.; It has formerly been assumed that RecA binds to the DNA template strand being copied. Instead, it is shown here that RecA protomers need to assemble in trans for pol V-catalyzed TLS to occur. Additional interactions with a RecA filament other than with the 3' proximal end in trans further stimulate synthesis. This mechanism resolves the paradox that, although RecA is absolutely required for SOS mutagenesis, RecA filaments assembled in cis on damaged DNA obstruct TLS. Biochemically, transactivation is indispensable for the polymerase activity and is suggested to reflect a distinct mutation regulatory mechanism in vivo. |
| Keyword | translesion synthesis; pol V; RecA; mutagenesis |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m102 |
| Rights | Schlacher, Katharina |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Schlacher-20061024 |
| Archival file | uscthesesreloadpub_Volume29/etd-Schlacher-20061024.pdf |
Description
| Title | Page 1 |
| Full text | THE MECHANISM OF DAMAGE-INDUCED MUTATIONS IN ESCHERICHIA COLI by Katharina Schlacher ______________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirement for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR BIOLOGY) December 2006 Copyright 2006 Katharina Schlacher |
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