ATR signaling mediates an S-phase checkpoint after inhibition of poly(ADP-ribose) polymerase activity

Human fibroblasts, capable of expressing a kinase-dead form of ATR (ATRkd), can be sensitized to the cytotoxic effects of methyl methanesulfonate (MMS) by the PARP inhibitor 4-amino-1,8-naphthalimide (4-AN). The combination of MMS + 4-AN results in accumulation of cells in S-phase of the cell cycle...

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Bibliographic Details
Published in:DNA repair 2007-06, Vol.6 (6), p.742-750
Main Authors: Horton, Julie K., Stefanick, Donna F., Kedar, Padmini S., Wilson, Samuel H.
Format: Article
Language:English
Subjects:
1-Naphthylamine - analogs & derivatives
1-Naphthylamine - pharmacology
ATR
Bacteriology
Base excision repair
Biological and medical sciences
Cell Cycle
Cell cycle, cell proliferation
Cell Division
Cell physiology
Cell signaling
Chk1
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Fibroblasts - metabolism
Flow Cytometry
Fundamental and applied biological sciences. Psychology
G2 Phase
Growth, nutrition, cell differenciation
Humans
Methyl Methanesulfonate
Microbiology
Molecular and cellular biology
Molecular genetics
Mutagenesis. Repair
Naphthalimides - pharmacology
PARP inhibitor
PARP-1
Phosphorylation
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - metabolism
Quinolones - pharmacology
S Phase
Signal Transduction
Time Factors
γH2AX
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Summary:Human fibroblasts, capable of expressing a kinase-dead form of ATR (ATRkd), can be sensitized to the cytotoxic effects of methyl methanesulfonate (MMS) by the PARP inhibitor 4-amino-1,8-naphthalimide (4-AN). The combination of MMS + 4-AN results in accumulation of cells in S-phase of the cell cycle and activation of Chk1. Inhibition of ATR activity by expression of ATRkd suppresses the S-phase accumulation and partially reverses the Chk1 phosphorylation. The results confirm involvement of an ATR-mediated damage response pathway in the MMS + 4-AN-induced S-phase cell cycle checkpoint in human fibroblasts. Consistent with this hypothesis, the inhibitors caffeine and UCN-01 also abrogate the ATR- and Chk1-mediated delay in progression through S-phase. In the absence of ATR-mediated signaling, MMS + 4-AN exposure results in a G 2/M arrest, rather than an S-phase checkpoint. Thus, whereas ATR mediates the S-phase response, it is not critical for arrest of cells in G 2/M.
ISSN:1568-7864
1568-7856
DOI:10.1016/j.dnarep.2006.12.015