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 -