The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA(2) GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to gamma-irradiation that was abolished by mutation of the NF-kappa B site in the Ipa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that Ipa2 is a DNA damage response gene upregulated by ATM via NF-kappa B. The resolution kinetics of the DNA damage marker gamma-H2AX in LPA-treated IEC-6 cells exposed to gamma-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA(2) delayed the resolution of gamma-H2AX. In LPA(2)-reconstituted MEF cells lacking LPA(1&3) the levels of gamma-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C(311)A/C(314)A/L(351)A mutation in the C-terminus of LPA(2) abrogated the effect of LPA on DNA repair. LPA(2) transcripts in Lin(-)Sca-1(+)c-Kit(+) enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual gamma-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA(2)-KO mice compared to WT mice. We found that gamma-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNF alpha. These findings identify ATX and LPA(2) as radiation-regulated genes that appear to play a physiological role in DNA repair. (C) 2015 Elsevier Inc All rights reserved.