Isabel Mellon,
Ph.D.
Associate Professor
Graduate Center for Toxicology
Phone:
(859) 257-6253
Fax:
(859) 257-7643
e-mail:
mellon@uky.edu
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Research Interests:
My laboratory
studies DNA repair mechanisms and we are interested in how alterations in
DNA repair impact disease processes. Nucleotide excision repair (NER) is a
major pathway for the removal of cyclobutane pyrimidine dimers (CPDs) and
6-4 photoproducts produced by UV light. It also removes a wide variety of
bulky adducts formed by chemical agents or carcinogens. It is a complex
multi-step process that is comprised of two subpathways in E. coli, yeast
and mammals. One subpathway is termed transcription-coupled repair (TCR)
which selectively removes lesions from the transcribed strands of
expressed genes. This subpathway of DNA repair I co-discovered with Philip
Hanawalt and colleagues. The other subpathway is termed global genome
repair (GGR) which removes lesions from the remainder of the genome. There
are 3 areas related to nucleotide excision repair that we are currently
investigating.
(1) Inherited defects in NER genes predispose humans
to cancer, predominantly skin cancer. This is clearly illustrated by the
disease xeroderma pigmentosum (XP). We are currently investigating whether
polymorphisms and/or acquired somatic mutations in NER genes can also be
involved in the etiology of certain types of cancer. We are focused on
skin cancer and lung cancer because the etiology of both forms of cancer
is clearly linked to agents that introduce bulky adducts that are
substrates for NER. We are
characterizing cell lines derived from different tumor types for
alterations in NER. In addition, we are searching for novel polymorphic
alleles and are carrying out structure/function studies to investigate the
functional significance of polymorphisms in NER genes.
(2) Certain chemotherapeutic agents introduce lesions
that are removed by nucleotide excision repair. The efficacy of some types
of chemotherapeutic agents in killing tumor cells may be related to
differences in the efficiency of nucleotide excision repair.
We are currently comparing nucleotide excision repair levels in
cell lines derived from different types of tumors that respond well to
certain chemotherapeutic agents vs those that respond poorly.
(3) TCR is clearly a subpathway of NER and is
generally observed as more rapid removal of lesions from the transcribed
strands of expressed genes compared with the nontranscribed strands. It
operates on a wide spectrum of lesions that generally block RNA polymerase
elongation. While the precise mechanism of TCR remains to be elucidated,
an early event likely involves blockage of the RNA polymerase complex at
lesions present in the transcribed strands of expressed genes.
We are currently investigating mechanisms of TCR in bacterial and
mammalian systems.
Recent
Publications:
Shin,
Y.S., Mellon,
I.
and Turker, M.S. (2002)
Multiple mutations are common at Mouse
Aprt in genotoxin exposed mismatch repair deficient cells. Oncogene
,
21:1768-76.
Mellon, I.,
Hock, T., Reid, R., Porter, P.C. and States, J.C. (2002) Polymorphisms in
the human xeroderma pigmentosum group A gene and their impact on cell
survival and nucleotide excision repair, DNA
REPAIR. 1, 531-546.
Alanazi,
M, Leadon, S.A., Mellon, I.
(2002) Global genome removal of thymine glycol in Escherichia coli
requires endonuclease III but the persistence of processed repair
intermediates rather than thymine glycol correlates with cellular
sensitivity to high doses of hydrogen peroxide. Nucleic
Acids Research 30, 4583-91.
Mellon,
I.
(2003) Transcription-coupled DNA repair. Encyclopedia of the Human
Genome, Nature Publishing.
Mellon,
I.
(2004)
Transcription-coupled repair: an overview. Encyclopedia of Biological
Chemistry, Elsevier Publishing, Volume 4.
Mellon, I.
(2005) Interactions of the Transcription Machinery with DNA Damage in
Prokaryotes, in DNA Damage Recognition, editors, Siede, W., Kow, Y.W. and Doetsch,
P.W.; Marcel-Dekker, Inc. pp159-171
Porter, P.C., Mellon,
I.
and States, J.C. (2005) XP-A cells
complemented with Arg228Gln and Val234Leu polymorphic XPA alleles repair
BPDE-induced DNA damage better than cells complemented with the wild type
allele. DNA REPAIR, 4, 341-349.
Mellon,
I.
(2005) Transcription-coupled repair: a complex affair, Special
Issues of Mutation Research in
press.
Earlier
Highlighted Publications:
Mellon,
I., Bohr, V.B.,
Smith
,
C.A.
, and Hanawalt, P.C. (1986) Preferential DNA repair of an active gene in
human cells. Proc. Natl. Acad.
Sci. USA 83, 8878-8882.
Mellon,
I., Spivak, G., and Hanawalt, P.C. (1987) Selective removal of
transcription‑ blocking DNA damage from the transcribed strand of
the mammalian DHFR gene. Cell
51, 241-249.
Mellon,
I. and Hanawalt, P.C. (1989) Induction of the Escherichia
coli lactose operon selectively increases repair of its transcribed
DNA strand. Nature
342, 95-98.
Mellon,
I. and Champe, G.N. (1996) Products of DNA mismatch repair genes mutS
and mutL are required for
transcription-coupled repair. Proc.
Natl. Acad. Sci. USA, Vol. 93, 1292-1297.
Mellon,
I., Rajpal, D., Koi, M., Boland, R., and Champe, G. (1996)
Transcription-coupled nucleotide excision repair deficiency associated
with mutations in human mismatch repair genes.
Science 272, 557-56.
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