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Vol. 12, Issue 5, 1199-1213, May 2001
and
*Department of Environmental Health, University of Cincinnati
College of Medicine, Cincinnati, Ohio, and §Queensland
Institute of Medical Research, The Bancroft Centre, PO Royal Brisbane
Hospital, Herston, Brisbane, Australia
Exposure to DNA-damaging agents triggers signal transduction
pathways that are thought to play a role in maintenance of genomic stability. A key protein in the cellular processes of nucleotide excision repair, DNA recombination, and DNA double-strand break repair
is the single-stranded DNA binding protein, RPA. We showed previously
that the p34 subunit of RPA becomes hyperphosphorylated as a delayed
response (4-8 h) to UV radiation (10-30 J/m2). Here we
show that UV-induced RPA-p34 hyperphosphorylation depends on expression
of ATM, the product of the gene mutated in the human genetic disorder
ataxia telangiectasia (A-T). UV-induced RPA-p34 hyperphosphorylation
was not observed in A-T cells, but this response was restored by ATM
expression. Furthermore, purified ATM kinase phosphorylates the p34
subunit of RPA complex in vitro at many of the same sites that are
phosphorylated in vivo after UV radiation. Induction of this DNA damage
response was also dependent on DNA replication; inhibition of DNA
replication by aphidicolin prevented induction of RPA-p34
hyperphosphorylation by UV radiation. We postulate that this pathway is
triggered by the accumulation of aberrant DNA replication
intermediates, resulting from DNA replication fork blockage by UV
photoproducts. Further, we suggest that RPA-p34 is hyperphosphorylated
as a participant in the recombinational postreplication repair of these
replication products. Successful resolution of these replication
intermediates reduces the accumulation of chromosomal aberrations that
would otherwise occur as a consequence of UV radiation.
Present address: Abbott Laboratories, 100 Abbott
Park Road, Abbott Park, Illinois 60064-3500.
Present address: Department of Medicinal Chemistry
and Pharmacognosy (M/C 781), College of Pharmacy, University of
Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-7231.
Present address: Department of Biochemistry,
University of Ireland, Galway, University Road, Galway, Ireland.
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