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

Balogh, A;Shimizu, Y;Lee, SC;Norman, DD;Gangwar, R;Bavaria, M;Moon, C;Shukla, P;Rao, R;Ray, R;Naren, AP;Banerjee, S;Banerje, S;Miller, DD;Balazs, L;Pelus, L;Tigyi, G;

In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 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 -irradiation that was abolished by mutation of the NF-B site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-B. The resolution kinetics of the DNA damage marker -H2AX in LPA-treated IEC-6 cells exposed to -irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of -H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of -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 C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 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 -H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that -irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNF. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair.