Abstract The XPC protein, which is mutated in xeroderma pigmentosum (XP) complementation group C (XP-C), is a lesion recognition factor in NER, but it has also been shown to interact with and stimulate DNA glycosylases, to act as transcriptional co-activator and on energy metabolism adaptation. We have previously demonstrated that XP-C cells show increased mitochondrial H2O2 production with a shift between respiratory complexes I and II, leading to sensitivity to mitochondrial stress. Here we report a marked decrease in expression of the transcriptional co-activator PGC-1α, a master regulator of mitochondrial biogenesis, in XP-C cells. A transcriptional role for XPC in PGC-1α expression was discarded, as XPC knockdown did not downregulate PGC-1α expression and XPC-corrected cells still showed lower PGC-1α expression. DNA methylation alone did not explain PGC-1α silencing. In four different XP-C cell lines tested, reduction of PGC-1α expression was detected in three, all of them carrying the c.1643_1644delTG mutation (ΔTG) in XPC. Indeed, all cell lines carrying XPC ΔTG mutation, whether homozygous or heterozygous, presented decreased PGC-1α expression. However, this alteration in gene expression was not exclusive to XPC ΔTG cell lines, for other non-related cell lines also showed altered PGC-1α expression. Moreover, PGC1-α expression did not correlate with expression levels of TFAM and SDHA, known PGC-1α target-genes. In turn, PPRC1, another member of the PGC family of transcription co-activators controlling mitochondrial biogenesis, displayed a good correlation between its expression in 10 cell lines and TFAM and SDHA. Nonetheless, PGC-1α knockdown led to a slight decrease of its target-gene protein level, TFAM, and subsequently of a mtDNA-encoded gene, MT-CO2. These results indicate that PGC-1α and PPRC1 cooperate as regulators of mitochondrial biogenesis and maintenance in fibroblasts.

中文翻译：

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PPRC1（而非 PGC-1α）水平与人真皮成纤维细胞中线粒体蛋白的表达直接相关

摘要 XPC 蛋白在色素性干皮病 (XP) 互补组 C (XP-C) 中发生突变，是 NER 中的病变识别因子，但它也已显示与 DNA 糖基化酶相互作用并刺激 DNA 糖基化酶，作为转录辅酶。 -激活剂和能量代谢适应。我们之前已经证明，XP-C 细胞的线粒体 H2O2 产量增加，呼吸复合体 I 和 II 之间发生变化，导致对线粒体应激的敏感性。在这里，我们报告了 XP-C 细胞中转录共激活因子 PGC-1α（线粒体生物发生的主要调节因子）的表达显着降低。XPC 在 PGC-1α 表达中的转录作用被丢弃，因为 XPC 敲低不会下调 PGC-1α 表达，并且 XPC 校正的细胞仍显示较低的 PGC-1α 表达。单独的 DNA 甲基化不能解释 PGC-1α 沉默。在测试的四种不同 XP-C 细胞系中，在三种中检测到 PGC-1α 表达降低，所有这些细胞系都携带 XPC 中的 c.1643_1644delTG 突变（ΔTG）。事实上，所有携带 XPC ΔTG 突变的细胞系，无论是纯合子还是杂合子，都呈现出降低的 PGC-1α 表达。然而，这种基因表达的改变并不是 XPC ΔTG 细胞系独有的，其他非相关细胞系也显示出 PGC-1α 表达的改变。此外，PGC1-α 表达与已知 PGC-1α 靶基因 TFAM 和 SDHA 的表达水平无关。反过来，PPRC1 是控制线粒体生物发生的转录共激活因子 PGC 家族的另一个成员，它在 10 个细胞系中的表达与 TFAM 和 SDHA 之间显示出良好的相关性。尽管如此，PGC-1α 敲低导致其靶基因蛋白水平 TFAM 和随后的 mtDNA 编码基因 MT-CO2 略有下降。这些结果表明 PGC-1α 和 PPRC1 作为成纤维细胞线粒体生物发生和维持的调节剂协同作用。