PDF(Pubmed)
Abstract：
Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common type of base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA. ATR inhibition in UNG-deficient cells blocks the repair of uracil-induced gaps, increasing replication fork collapse and cell death. Notably, a subset of cancer cells upregulates UNG2 to suppress genomic uracil and limit RS, and these cancer cells are hypersensitive to co-treatment with ATR inhibitors and drugs increasing genomic uracil. These results reveal unprocessed genomic uracil as an unexpected source of RS and a targetable vulnerability of cancer cells.
摘要：
DNA中碱基的改变构成基因组不稳定性的主要来源。据信碱基改变引发碱基切除修复(BER)，产生干扰DNA复制的DNA修复中间体。这里,我们显示基因组尿嘧啶，一种常见的碱基改变，诱导DNA复制应激(RS)而不被BER处理。在没有尿嘧啶DNA糖基化酶（UNG）的情况下，基因组尿嘧啶积累到高水平，DNA复制叉慢下来，PrimPol介导的再灌注增强，在新生DNA中产生单链缺口。UNG缺陷细胞中的ATR抑制阻断尿嘧啶诱导的间隙的修复，增加复制叉崩溃和细胞死亡。值得注意的是,一部分癌细胞上调UNG2以抑制基因组尿嘧啶并限制RS，这些癌细胞对ATR抑制剂和增加基因组尿嘧啶的药物共同治疗过敏。这些结果揭示了未加工的基因组尿嘧啶作为RS的意外来源和癌细胞的可靶向脆弱性。
