TY - JOUR
T1 - Cellular pathways for DNA repair and damage tolerance of formaldehyde-induced DNA-protein crosslinks
AU - de Graaf, Bendert
AU - Clore, Adam
AU - McCullough, Amanda K.
N1 - Funding Information:
We thank Robb Moses (OHSU), Peter McHugh (University of Oxford) and Leona Samson (MIT) for the generous gifts of yeast strains. We would also like to thank Christian Dan and Erik Bom for technical assistance. We are grateful to R. Stephen Lloyd, Irina Minko, and Anuradha Kumari for valuable comments and critically reading the manuscript. This work was supported in part by NIH RO1 CA106858 and NIH PO1 ES05355.
PY - 2009/10/2
Y1 - 2009/10/2
N2 - Although it is well established that DNA-protein crosslinks are formed as a consequence of cellular exposure to agents such as formaldehyde, transplatin, ionizing and ultraviolet radiation, the biochemical pathways that promote cellular survival via repair or tolerance of these lesions are poorly understood. To investigate the mechanisms that function to limit DNA-protein crosslink-induced cytotoxicity, the Saccharomyces cerevisiae non-essential gene deletion library was screened for increased sensitivity to formaldehyde exposure. Following low dose, chronic exposure, strains containing deletions in genes mediating homologous recombination showed the greatest sensitivity, while under the same exposure conditions, deletions in genes associated with nucleotide excision repair conferred only low to moderate sensitivities. However, when the exposure regime was changed to a high dose acute (short-term) formaldehyde treatment, the genes that conferred maximal survival switched to the nucleotide excision repair pathway, with little contribution of the homologous recombination genes. Data are presented which suggest that following acute formaldehyde exposure, repair and/or tolerance of DNA-protein crosslinks proceeds via formation of nucleotide excision repair-dependent single-strand break intermediates and without a detectable accumulation of double-strand breaks. These data clearly demonstrate a differential pathway response to chronic versus acute formaldehyde exposures and may have significance and implications for risk extrapolation in human exposure studies.
AB - Although it is well established that DNA-protein crosslinks are formed as a consequence of cellular exposure to agents such as formaldehyde, transplatin, ionizing and ultraviolet radiation, the biochemical pathways that promote cellular survival via repair or tolerance of these lesions are poorly understood. To investigate the mechanisms that function to limit DNA-protein crosslink-induced cytotoxicity, the Saccharomyces cerevisiae non-essential gene deletion library was screened for increased sensitivity to formaldehyde exposure. Following low dose, chronic exposure, strains containing deletions in genes mediating homologous recombination showed the greatest sensitivity, while under the same exposure conditions, deletions in genes associated with nucleotide excision repair conferred only low to moderate sensitivities. However, when the exposure regime was changed to a high dose acute (short-term) formaldehyde treatment, the genes that conferred maximal survival switched to the nucleotide excision repair pathway, with little contribution of the homologous recombination genes. Data are presented which suggest that following acute formaldehyde exposure, repair and/or tolerance of DNA-protein crosslinks proceeds via formation of nucleotide excision repair-dependent single-strand break intermediates and without a detectable accumulation of double-strand breaks. These data clearly demonstrate a differential pathway response to chronic versus acute formaldehyde exposures and may have significance and implications for risk extrapolation in human exposure studies.
KW - DNA repair
KW - DNA-protein crosslinks
KW - Formaldehyde
KW - Homologous recombination
KW - Nucleotide excision repair
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U2 - 10.1016/j.dnarep.2009.06.007
DO - 10.1016/j.dnarep.2009.06.007
M3 - Article
C2 - 19625222
AN - SCOPUS:70149098475
SN - 1568-7864
VL - 8
SP - 1207
EP - 1214
JO - DNA Repair
JF - DNA Repair
IS - 10
ER -