Rights statement: This is the author’s version of a work that was accepted for publication in DNA Repair. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in DNA Repair, 33, 2015 DOI: 10.1016/j.dnarep.2015.06.008
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Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Diadenosine 5′, 5′′′-P1,P4-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication.
AU - Marriott, Andrew S.
AU - Copeland, Nikki
AU - Cunningham, Ryan
AU - Wilkinson, Mark C.
AU - McLennan, Alexander G.
AU - Jones, Nigel J.
N1 - This is the author’s version of a work that was accepted for publication in DNA Repair. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in DNA Repair, 33, 2015 DOI: 10.1016/j.dnarep.2015.06.008
PY - 2015/9
Y1 - 2015/9
N2 - The level of intracellular diadenosine 5, 5-P1,P4-tetraphosphate (Ap4A) increases several fold in mammalian cells treated with non-cytotoxic doses of interstrand DNA-crosslinking agents such as mitomycinC. It is also increased in cells lacking DNA repair proteins including XRCC1, PARP1, APTX and FANCG,while >50-fold increases (up to around 25 M) are achieved in repair mutants exposed to mitomycin C.Part of this induced Ap4A is converted into novel derivatives, identified as mono- and di-ADP-ribosylatedAp4A. Gene knockout experiments suggest that DNA ligase III is primarily responsible for the synthesisof damage-induced Ap4A and that PARP1 and PARP2 can both catalyze its ADP-ribosylation. Degrada-tive proteins such as aprataxin may also contribute to the increase. Using a cell-free replication system,Ap4A was found to cause a marked inhibition of the initiation of DNA replicons, while elongation wasunaffected. Maximum inhibition of 70–80% was achieved with 20 M Ap4A. Ap3A, Ap5A, Gp4G and ADP-ribosylated Ap4A were without effect. It is proposed that Ap4A acts as an important inducible ligand inthe DNA damage response to prevent the replication of damaged DNA.
AB - The level of intracellular diadenosine 5, 5-P1,P4-tetraphosphate (Ap4A) increases several fold in mammalian cells treated with non-cytotoxic doses of interstrand DNA-crosslinking agents such as mitomycinC. It is also increased in cells lacking DNA repair proteins including XRCC1, PARP1, APTX and FANCG,while >50-fold increases (up to around 25 M) are achieved in repair mutants exposed to mitomycin C.Part of this induced Ap4A is converted into novel derivatives, identified as mono- and di-ADP-ribosylatedAp4A. Gene knockout experiments suggest that DNA ligase III is primarily responsible for the synthesisof damage-induced Ap4A and that PARP1 and PARP2 can both catalyze its ADP-ribosylation. Degrada-tive proteins such as aprataxin may also contribute to the increase. Using a cell-free replication system,Ap4A was found to cause a marked inhibition of the initiation of DNA replicons, while elongation wasunaffected. Maximum inhibition of 70–80% was achieved with 20 M Ap4A. Ap3A, Ap5A, Gp4G and ADP-ribosylated Ap4A were without effect. It is proposed that Ap4A acts as an important inducible ligand inthe DNA damage response to prevent the replication of damaged DNA.
KW - Diadenosine tetraphosphate
KW - DNA damage
KW - DNA replication
KW - ADP-ribosylation
KW - Cell signaling
U2 - 10.1016/j.dnarep.2015.06.008
DO - 10.1016/j.dnarep.2015.06.008
M3 - Journal article
VL - 33
SP - 90
EP - 100
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
ER -