Ctf4 is a conserved replisome component with multiple roles in DNA metabolism. To investigate connections between Ctf4-mediated processes involved in drug resistance, we conducted a suppressor screen of ctf4Δ sensitivity to the methylating agent MMS. We uncovered that mutations in Dpb3 and Dpb4 components of polymerase ε result in the development of drug resistance in ctf4Δ via their histone-binding function. Alleviated sensitivity to MMS of the double mutants was not associated with rescue of ctf4Δ defects in sister chromatid cohesion, replication fork architecture, or template switching, which ensures error-free replication in the presence of genotoxic stress. Strikingly, the improved viability depended on translesion synthesis (TLS) polymerase-mediated mutagenesis, which was drastically increased in ctf4 dpb3 double mutants. Importantly, mutations in Mcm2–Ctf4–Polα and Dpb3–Dpb4 axes of parental (H3–H4)₂ deposition on lagging and leading strands invariably resulted in reduced error-free DNA damage tolerance through gap filling by template switch recombination. Overall, we uncovered a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance.

中文翻译：

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复制链上的亲本组蛋白沉积促进无错误 DNA 损伤耐受性并调节耐药性

Ctf4 是一种保守的复制体成分，在 DNA 代谢中具有多种作用。为了研究 Ctf4 介导的耐药过程之间的联系，我们对甲基化剂 MMS的ctf4 Δ 敏感性进行了抑制筛选。我们发现聚合酶 ε 的 Dpb3 和 Dpb4 成分的突变导致ctf4 Δ 通过其组蛋白结合功能产生耐药性。双突变体对 MMS 的敏感性减轻与ctf4的拯救无关Δ 姐妹染色单体内聚力、复制叉结构或模板转换的缺陷，确保在存在基因毒性压力的情况下无错误复制。引人注目的是，提高的生存能力取决于跨损伤合成 (TLS) 聚合酶介导的诱变，这在ctf4 dpb3双突变体中急剧增加。重要的是，Mcm2–Ctf4–Polα 和 Dpb3–Dpb4 亲本 (H3–H4) 轴的突变₂通过模板开关重组的间隙填充，在滞后链和前导链上的沉积总是导致无错误 DNA 损伤耐受性降低。总体而言，我们发现了一种基于染色质的耐药机制，其中复制叉通过后亲本组蛋白转移的缺陷会损害无错误重组旁路，并导致 TLS 介导的诱变和耐药性的上调。