Many human diseases are associated with alleles that can be as simple as single-nucleotide changes to copy-number variants, gene fusions and translocations. The wealth of recent whole-genome sequencing has led to the realization that recent mutation play as important a role as variations that arose in distant ancestors. These disease-associated alleles can arise from mutational events that are provoked by errors arising In a number of ways during DNA replication, including (a) ionizing radiation, (b) the excision of mobile genetic elements, (c) the formation of double strand breaks (DSBs) at stalled replication forks, (d) replication slippage in DNA sequences that form alternative secondary structures, (e) conflicts between replication forks and the transcription machinery, and (f) the filling-in of singe-stranded DNA. This Program Project focuses on these different sources of mutation in a highly interactive set of projects that link researchers at Brandeis University and Tufts University studying three powerful model organisms: the bacterium pound coli, the single cell eukaryote, the budding yeast S. cerevisiae, and the metazoan, fruit fly D. melanogaster. Our goal is to understand in great detail the way several important types of mutations arise and to identify transcription, replication and DNA repair factors whose defects elevate their appearance. Importantly, the proposed core facilities will enable us to expand our studies beyond what has been previously possible and to test our models on genome-wide scales. Through the Core Facilities proposed as an integral part of this Program Project, participants will apply state-of-the-art high-throughput technologies to their studies of repair-associated mutagenesis. Automation of data collection and analysis will enable each investigator to expand the scope of their Investigation and will establish new standard procedures for the study of mutation generation. Interactions will be fostered by bi-monthly meetings of the entire labs from the two institutions, as well as at a retreat attended by two outside expert advisors.

Public Health Relevance

It is of paramount importance to understand the origins of mutations associated with human disease. Recent studies have shown that pre-cancerous cells have elevated impairments of DNA replication and the appearance of chromosome breaks. Our studies of model organisms makes it possible to elucidate in much greater detail than is now possible with mammalian cells the mechanisms of mutagenesis associated with replication fork stalling and the repair of chromosomal damage. The ability to confirm and extend findings in one model system to others will be of great benefit in understanding the common aspects of damage- associated mutagenesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-Q (40))
Program Officer
Janes, Daniel E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brandeis University
Schools of Arts and Sciences
United States
Zip Code
Dwivedi, Gajendrahar; Haber, James E (2018) Assaying Mutations Associated With Gene Conversion Repair of a Double-Strand Break. Methods Enzymol 601:145-160
Kononenko, Artem V; Ebersole, Thomas; Vasquez, Karen M et al. (2018) Mechanisms of genetic instability caused by (CGG)n repeats in an experimental mammalian system. Nat Struct Mol Biol 25:669-676
McGinty, Ryan J; Mirkin, Sergei M (2018) Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics. Trends Genet 34:448-465
Polleys, Erica J; Freudenreich, Catherine H (2018) Methods to Study Repeat Fragility and Instability in Saccharomyces cerevisiae. Methods Mol Biol 1672:403-419
Gallagher, Danielle N; Haber, James E (2018) Repair of a Site-Specific DNA Cleavage: Old-School Lessons for Cas9-Mediated Gene Editing. ACS Chem Biol 13:397-405
Radchenko, Elina A; McGinty, Ryan J; Aksenova, Anna Y et al. (2018) Quantitative Analysis of the Rates for Repeat-Mediated Genome Instability in a Yeast Experimental System. Methods Mol Biol 1672:421-438
Moore, Anthony; Dominska, Margaret; Greenwell, Patricia et al. (2018) Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences. Genetics 209:425-438
Lemos, Brenda R; Kaplan, Adam C; Bae, Ji Eun et al. (2018) CRISPR/Cas9 cleavages in budding yeast reveal templated insertions and strand-specific insertion/deletion profiles. Proc Natl Acad Sci U S A 115:E2040-E2047
Haber, James E (2018) DNA Repair: The Search for Homology. Bioessays 40:e1700229
Polleys, Erica J; House, Nealia C M; Freudenreich, Catherine H (2017) Role of recombination and replication fork restart in repeat instability. DNA Repair (Amst) 56:156-165

Showing the most recent 10 out of 39 publications