Pif1 family helicases promote mutation avoidance during DNA replication.
Pif1 family helicases promote mutation avoidance during DNA replication.
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DOI：
10.1093/nar/gkac1127
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发表时间：
2022-12
影响因子：
14.9
通讯作者：
Zhi-Xiong Zhou;Cindy Follonier;S. Lujan;Adam B. Burkholder;V. Zakian;T. Kunkel
中科院分区：
文献类型：
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作者：
Zhi-Xiong Zhou;Cindy Follonier;S. Lujan;Adam B. Burkholder;V. Zakian;T. Kunkel
Pif 1家族5' → 3' DNA解旋酶对于复制叉进展和基因组稳定性是重要的。芽殖酵母酿酒酵母（Saccharomyces cerevisiae）编码两种Pif1家族解旋酶Rrm3和Pif1，这两种解旋酶都是多功能的。在这里，我们描述了新的功能RRM3在促进DNA复制过程中避免突变。我们发现，RRM3的缺失导致DNA聚合酶Pols β和δ产生的自发突变增加，这些突变受到DNA错配修复的影响。RRM3的缺失也引起第四B家族DNA聚合酶Pol β的更高的诱变。通过全基因组分析，我们发现RRM3缺失导致的突变后果因基因组位点而异。Rrm3促进了DNA复制的准确性，通过Pols β和δ在整个基因组中，它是特别重要的，以防止在tRNA基因的Pols β依赖性诱变。此外，Rrm3的突变避免依赖于其解旋酶活性，Pif1在抑制突变中充当Rrm3的备份。我们提出的证据表明，人类细胞中唯一的人类Pif1家族解旋酶也可能促进复制保真度，这表明Pif1家族解旋酶在突变避免中的作用可能是进化上保守的，这是其潜在的肿瘤抑制功能的潜在机制。
Pif1 family 5' → 3' DNA helicases are important for replication fork progression and genome stability. The budding yeast Saccharomyces cerevisiae encodes two Pif1 family helicases, Rrm3 and Pif1, both of which are multi-functional. Here we describe novel functions for Rrm3 in promoting mutation avoidance during DNA replication. We show that loss of RRM3 results in elevated spontaneous mutations made by DNA polymerases Pols ϵ and δ, which are subject to DNA mismatch repair. The absence of RRM3 also causes higher mutagenesis by the fourth B-family DNA polymerase Pol ζ. By genome-wide analysis, we show that the mutational consequences due to loss of RRM3 vary depending on the genomic locus. Rrm3 promotes the accuracy of DNA replication by Pols ϵ and δ across the genome, and it is particularly important for preventing Pol ζ-dependent mutagenesis at tRNA genes. In addition, mutation avoidance by Rrm3 depends on its helicase activity, and Pif1 serves as a backup for Rrm3 in suppressing mutagenesis. We present evidence that the sole human Pif1 family helicase in human cells likely also promotes replication fidelity, suggesting that a role for Pif1 family helicases in mutation avoidance may be evolutionarily conserved, a possible underlying mechanism for its potential tumor-suppressor function.