Nicks are the most frequent form of DNA damage and a potential source of mutagenesis in human cells. By deep sequencing, we have identified factors and pathways that promote and limit mutagenic repair at targeted nicks. BRCA2 inhibits all categories of mutational events at nicks, including indels, SNVs and HDR. DNA2 and RPA promote 5' resection. Most insertions at nicks consist of a single C incorporated opposite the nick by the translesion polymerase REV1. DNA2 and REV3 inhibit these 1 bp insertions; and DNA2 also inhibits 1 bp deletions. Longer deletions are stimulated by DNA2, REV7 and POLQ. Strikingly, POLQ generates most SNVs at both nicks and double-strand breaks. These results identify mutagenic signatures of DNA2, REV1, REV3, REV7 and POLQ at nicks and highlight the potential for nicks to promote mutagenesis, especially in BRCA-deficient cells.

中文翻译：

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靶向DNA缺口诱变的途径和特征

缺口是最常见的DNA损伤形式，并且是人类细胞中潜在的诱变来源。通过深度测序，我们确定了促进和限制针对靶切点的诱变修复的因素和途径。BRCA2抑制切口处的所有类别的突变事件，包括插入缺失，SNV和HDR。DNA2和RPA促进5'切除。切口处的大多数插入物由与跨切口聚合酶REV1相对于切口的单个C组成。DNA2和REV3抑制了这些1 bp的插入；DNA2也抑制1 bp的缺失。DNA2，REV7和POLQ刺激更长的缺失。令人惊讶的是，POLQ会在刻痕和双链断裂处生成大多数SNV。这些结果确定了缺口处DNA2，REV1，REV3，REV7和POLQ的诱变特征，并突出了缺口促进诱变的潜力，