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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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