Transcriptional changes in the absence of nth-1, xpa-1 and nth-1;xpa-1

Background: The ability of an organism to repair damages to DNA is inextricably linked to aging and cancer. We have characterized and compared the transcriptome of C. elegans mutants deficient in DNA base excision repair, nucleotide excision repair or both to elucidate the transcriptional changes incurred by the reduction of these repair pathways. Results: The gene expression signatures from nth-1, xpa-1 and nth-1;xpa-1 are deciphered. We find that the single mutants are more similar in overall transcriptomic activity compared to the double mutant and their corresponding wild-type (N2). Interestingly, of the enriched Gene Ontology terms for respective mutants are aging and proteolysis for nth-1, aging, energy production and unfolded protein response for xpa-1, and DNA repair and regulation of M-phase for nth-1;xpa-1. We also find striking similarities between the biological processes found to be enriched in the single mutants, which show a shared response in genes associated with aging and insulin signaling. Loss of either BER or NER induces an oxidative stress response, but does not confer resistance to heat shock. Conclusion: Taken together, our study provides a general overview about the global transcriptional changes in the absence of nth-1, xpa-1 and nth-1;xpa-1. Our results also point to a two-tiered global response to combat the effects of decreased DNA repair capacity.背景：生物体修复DNA损伤的能力与衰老和癌症密不可分。本研究对碱基切除修复（base excision repair, BER）、核苷酸切除修复（nucleotide excision repair, NER）单缺陷或双缺陷的秀丽隐杆线虫（C. elegans）突变体的转录组进行表征与比较，以阐明这些修复通路功能减弱所引发的转录组变化。 结果：本研究解析了nth-1、xpa-1及nth-1;xpa-1的基因表达特征。相较于双突变体及其对应的野生型（N2），单突变体的整体转录组活性更为相似。有趣的是，各突变体富集的基因本体（Gene Ontology, GO）术语分别为：nth-1富集衰老与蛋白水解过程，xpa-1富集衰老、能量产生与未折叠蛋白反应（unfolded protein response, UPR）过程，nth-1;xpa-1富集DNA修复与M期调控过程。本研究还发现，两个单突变体富集的生物学过程存在显著相似性，二者均存在与衰老及胰岛素信号通路相关基因的共应答现象。无论是BER还是NER功能缺失，均会诱导氧化应激反应，但无法赋予生物体热激抗性。 结论：综上，本研究全面概述了nth-1、xpa-1及nth-1;xpa-1缺失情况下的全局转录组变化。本研究结果还揭示了一种应对DNA修复能力下降的双层全局应答机制。