Ribonucleotide excision repair is essential to prevent skin cancer [CD49f+ epidermal cells]

Large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase due to imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Complete lack of RER is embryonically lethal. Partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here we establish that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage, epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals develop keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. Compromised RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.

在细胞周期S期，由于复制性DNA聚合酶无法精准区分核糖核苷三磷酸，大量核糖核苷酸会被整合至真核生物核基因组中。核糖核苷酸是增殖细胞中最常见的DNA损伤类型，可破坏DNA结构稳定性；而进化保守的DNA修复机制——核糖核苷酸切除修复（ribonucleotide excision repair, RER）——负责清除这些整合的核糖核苷酸。完全缺失RER会导致胚胎致死。编码核糖核酸酶H2（RNase H2，RER启动必需的酶）亚基的基因发生部分功能丧失突变，会引发与系统性红斑狼疮（SLE）相关的I型干扰素病——艾卡迪-古捷雷斯综合征（Aicardi-Goutières syndrome）。本研究证实，在小鼠表皮中选择性失活RER，可引发自发性DNA损伤，并出现伴随毛囊干细胞丢失与毛囊功能受损的表皮过度增殖。尽管伴随强效I型干扰素产生与皮肤炎症反应，该模型小鼠仍会完全外显地出现角质形成细胞上皮内瘤变与侵袭性鳞状细胞癌。RER介导的基因组维持功能受损，可能是人类癌症中一项重要的促肿瘤机制。