Michael Fasullo, Ph.D.
Senior Scientist, Ordway Research Institute
Associate Professor of Biomedical Sciences, State University of New York at Albany
Adjunct Professor in the Center or Immunology and Microbial Diseases, Albany Medical College

DNA Repair Laboratory

Phone: (518) 641-6467
Fax: (518) 641-6304
mfasullo@ordwayresearch.org

Research Focus

The goal of Dr. Fasullo’s laboratory is to understand how responses induced by DNA damage suppress genomic instability. DNA damage-induced checkpoints are surveillance mechanisms that ensure that genomic integrity is maintained before sister chromatids are segregated to daughter cells. Failure to arrest the cell cycle or induce gene expression in response to DNA damage has been postulated to increase genetic instability and lead to carcinogenesis. The DNA Repair Laboratory team is interested in understanding the genetic control of genomic stability after exposure to radiation or resulting from folate (thymidylate) depletion. They use Saccharomyces cerevisiae (budding yeast) as a model system. The team has constructed specific yeast strains to measure gene conversion between heteroalleles, translocations, inversions, and sister-chromatid exchanges (SCEs) using prototrophic selections.

Since sister chromatids are preferred substrates for recombinational repair of X-ray induced damage, the laboratory has been particularly interested in understanding the role of cell cycle checkpoints in facilitating sister chromatid recombination and suppressing chromosomal rearrangements. Genes involved in the DNA damage-induced checkpoint pathways include those that sense DNA damage, such as RAD9, those that transmit the DNA damage signal, such as the ATM/ATR homologue MEC1, and those that trigger G₂ arrest such as PDS1, and RAD53. In addition, MEC1 is required for DNA damage inducibility of RNR (ribonucleotide reductase) and the RecA homologue RAD51. Rad51 mutants are deficient in DNA damage-associated SCE and exhibit higher frequencies of DNA damage-associated translocations. The DNA Repair Laboratory has shown that the RAD9-dependent G₂ checkpoint reduces DNA-damage associated translocations but facilitates X-ray associated SCE. However, MEC1, which is required for both the S and G₂ checkpoints, is required for DNA damage-associated SCE and to suppress both heteroallelic gene conversion and translocations. They are now investigating the role of downstream targets of MEC1 to understand which branch of the checkpoint pathway is critical for maintaining genomic stability, and whether genes that reduce frequencies of chromosomal rearrangements participate in the same genetic pathways. The team is also testing whether over-expression of either RNR1 or RAD51 can suppress particular mec1 recombination phenotypes.

Cells exposed to the folate antagonist methotrexate (MTX) also exhibit genetic instability. Folate deficiencies are correlated to the increased incidence of birth defects. MTX exposure results in thymidine depletion and increased incorporation of uracil into DNA. One hypothesis is that DNA repair pathways that excise uracil from DNA also promote recombination by indirectly generating double-strand breaks. The laboratory is also investigating the role of cell cycle checkpoints and other DNA repair genes in suppressing MTX-associated genetic instability.

Selected Publications

www.pubmed.com

Dong, Z. and Fasullo, M. Multiple recombination pathways for spontaneous and DNA damage-associated sister chromatid exchange in Saccharomyces cerevisiae : Role of RAD1 and the RAD52 epistasis group genes. Nucleic Acids Res. 31:2576-2585. 2003

Keller-Seitz, M., Certa, Ulrich, Sengstag, C., Wurgler, F., Sun, M., and Fasullo , M. Genome wide transcriptional response of the yeast Saccharomcyes cerevisiae to the carcinogen Aflatoxin B 1 : Indications of recombinational repair involving RAD51 and RAD1 . Molecular Biology of the Cell. 15:4321-4336, 2004

DeMase, D., Zeng, L., Cera, C. and Fasullo, M. The Saccharomyces cerevisiae PDS1 and RAD9 checkpoint genes control different DNA double-strand break repair pathways. DNA Repair 4:59-69, 2005

Fasullo, M . St. Amour, C., and Zeng, L., Enhanced stimulation of chromosomal translocations and sister chromatid exchanges by either HO-induced double-strand breaks or ionizing radiation in Saccharomyces cerevisiae yku70 mutants (Mutat. Research, in press).

Fasullo, M ., Sun, M., Dong, Z., Saccharomyces cerevisiae RAD53 (CHK2) but not CHK1 is required for double-strand break-initiated SCE and DNA damage-associated SCE after exposure to X rays and chemical agents. (DNA Repair, in press).

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