Recombinational repair is important for cell survival and stability of genetic material. In humans, inefficiency of repair has been associated with cancer proneness, neurological and developmental defects and premature aging. Recent evidence suggests that, in all cells, every round of replication requires some form of replication fork repair. In this proposed study, we will address several important questions in prokaryotic and eukaryotic recombination that have relevance to replication fork repair in every organism. (1) How do the RecA paralog proteins facilitate recombination? Every organism appears to employ a RecA-/Rad51 orthologous strand exchange protein and at least one other RecA/Rad51 paralog protein. What are the paralogs doing? We will use a combined biochemical and genetic approach to address the role of the RecA paralog protein, RadA/Sms in genetic recombination of E. coli. (2) What branched DNA molecules are intermediates of recombination and which enzymes resolve them? Our knowledge of the enzymes that process branched DNA intermediates of recombination is incomplete. We will assay whether the RuvC-related protein of E. coli, YqgF, is involved in recombinational repair and can catalyze cleavage of branched molecules predicted by recombination mechanisms. (3) What factors mediate template-switch repair? This is a recombinational mechanism that leads to sister chromosome exchange without the requirement for a strand-exchange protein such as RecA. Our previous work identified the first two factors involved in template-switch repair of E. coli, the chaperone DnaK and the gamma/tau subunit of DNA polymerase III, DnaX. What other factors enable this reaction? Using genetic analysis, we will test the involvement of proteins of the replisome and seek factors presently unknown. Replication fork repair is important for cell survival and stability of genes. In humans, inefficiency of repair has been associated with cancer proneness, neurological and developmental defects and premature aging. This proposal seeks to understand the mechanisms of replication fork repair.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics A Study Section (MGA)
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Hagan, Ann A
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Brandeis University
Schools of Arts and Sciences
United States
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Lovett, Susan T (2017) Template-switching during replication fork repair in bacteria. DNA Repair (Amst) 56:118-128
Cooper, Deani L; Lovett, Susan T (2016) Recombinational branch migration by the RadA/Sms paralog of RecA in Escherichia coli. Elife 5:
Cooper, Deani L; Boyle, Daniel C; Lovett, Susan T (2015) Genetic analysis of Escherichia coli?RadA: functional motifs and genetic interactions. Mol Microbiol 95:769-79
Brown, Laura T; Sutera Jr, Vincent A; Zhou, Shen et al. (2015) Connecting Replication and Repair: YoaA, a Helicase-Related Protein, Promotes Azidothymidine Tolerance through Association with Chi, an Accessory Clamp Loader Protein. PLoS Genet 11:e1005651
Anand, Ranjith P; Lovett, Susan T; Haber, James E (2013) Break-induced DNA replication. Cold Spring Harb Perspect Biol 5:a010397
Seier, Tracey; Zilberberg, Gal; Zeiger, Danna M et al. (2012) Azidothymidine and other chain terminators are mutagenic for template-switch-generated genetic mutations. Proc Natl Acad Sci U S A 109:6171-4
Seier, Tracey; Padgett, Dana R; Zilberberg, Gal et al. (2011) Insights into mutagenesis using Escherichia coli chromosomal lacZ strains that enable detection of a wide spectrum of mutational events. Genetics 188:247-62
Lovett, Susan T (2011) The DNA Exonucleases of Escherichia coli. EcoSal Plus 4:
Cooper, Deani L; Lovett, Susan T (2011) Toxicity and tolerance mechanisms for azidothymidine, a replication gap-promoting agent, in Escherichia coli. DNA Repair (Amst) 10:260-70
Merrikh, Houra; Ferrazzoli, Alexander E; Lovett, Susan T (2009) Growth phase and (p)ppGpp control of IraD, a regulator of RpoS stability, in Escherichia coli. J Bacteriol 191:7436-46

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