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DNA Repair (Amst). 2015 Sep;33:90-100. doi: 10.1016/j.dnarep.2015.06.008. Epub 2015 Jun 29.

Diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication.

Author information

1
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
2
Division of Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YG, UK.
3
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: agmclen@liv.ac.uk.

Abstract

The level of intracellular diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) increases several fold in mammalian cells treated with non-cytotoxic doses of interstrand DNA-crosslinking agents such as mitomycin C. It is also increased in cells lacking DNA repair proteins including XRCC1, PARP1, APTX and FANCG, while >50-fold increases (up to around 25 μM) 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-ribosylated Ap4A. Gene knockout experiments suggest that DNA ligase III is primarily responsible for the synthesis of damage-induced Ap4A and that PARP1 and PARP2 can both catalyze its ADP-ribosylation. Degradative 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 was unaffected. Maximum inhibition of 70-80% was achieved with 20 μM Ap4A. Ap3A, Ap5A, Gp4G and ADP-ribosylated Ap4A were without effect. It is proposed that Ap4A acts as an important inducible ligand in the DNA damage response to prevent the replication of damaged DNA.

KEYWORDS:

ADP-ribosylation; Cell signaling; DNA damage; DNA replication; Diadenosine tetraphosphate

PMID:
26204256
DOI:
10.1016/j.dnarep.2015.06.008
[Indexed for MEDLINE]

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