Abstract
XPD is an evolutionarily conserved protein critical for DNA repair, transcription, cell cycle, and chromosome segregation. XPD mutations result in complex genetic diseases, including xeroderma pigmentosum (XP). XPD is also implicated in protecting cells from oxidative stress but has not been linked to specific metabolic gene functions. Here, we report an intriguing genetic interaction between Drosophila Xpd and the scheggia (sea) gene encoding the mitochondrial citrate transporter. We show that the reduced eye size by Xpd RNAi in Drosophila is partially restored by the knockdown of sea. sea RNAi suppresses ectopic cell death and DNA damages resulting from Xpd knockdown. To test whether this negative relationship between Xpd and sea can be recapitulated in human cells, we examined the effects of CTPI-2, an inhibitor of the human citrate transporter SLC25A1, on the survival of XPD mutant cells (HD2) carrying the R683W point mutation (XPDR683W). CTPI-2 reduced the survival of UV-irradiated HeLa cells used as control. In contrast, the same level of CTPI-2 increased the viability of HD2 mutant cells exposed to a wide range of UV doses. In response to UV irradiation, HD2 cells are defective in unscheduled DNA synthesis (UDS). CTPI-2 increased the UDS response in HD2 cells. These data indicate that UV-induced DNA damage and lethality of human XPD mutant cells can be suppressed by inhibiting SLC25A1 by CTPI-2, consistent with the genetic interaction between Xpd and sea in Drosophila. This work suggests that XPD is antagonistically related to SLC25A1, and the citrate transporter may be a therapeutic target for alleviating XP syndrome.
Keywords:
Cell survival; Citrate transporter; DNA repair; Drosophila; Growth; SLC25A1; Scheggia gene; UV damage; XPD.