Genomic DNA is continuously challenged by endogenous and exogenous sources of damage. The resulting lesions may act as physical blocks to DNA replication, necessitating repair mechanisms to be intrinsically coupled to the DNA replisome machinery. DNA damage tolerance (DDT) is comprised of translesion synthesis (TLS) and template switch (TS) repair processes that allow the replisome to bypass of bulky DNA lesions and complete DNA replication. How the replisome orchestrates which DDT repair mechanism becomes active at replication blocks has remained enigmatic. In this issue of Genes & Development, Dolce and colleagues (pp. 167–179) report that parental histone deposition by replisome components Ctf4 and Dpb3/4 promotes TS while suppressing error-prone TLS. Deletion of Dpb3/4 restored resistance to DNA-damaging agents in ctf4Δ cells at the expense of synergistic increases in mutagenesis due to elevated TLS. These findings illustrate the importance of replisome-directed chromatin maintenance to genome integrity and the response to DNA-damaging anticancer therapeutics.

中文翻译：

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DNA损伤耐受复制体依赖性控制的内部运作

基因组 DNA 不断受到内源性和外源性损伤的挑战。由此产生的损伤可能会成为 DNA 复制的物理障碍，从而需要将修复机制与 DNA 复制体机制本质上耦合起来。DNA 损伤耐受 (DDT) 由跨损伤合成 (TLS) 和模板转换 (TS) 修复过程组成，允许复制体绕过大量 DNA 损伤并完成 DNA 复制。复制体如何协调 DDT 修复机制在复制块上变得活跃仍然是个谜。在本期《Genes & Development》中，Dolce 及其同事（第 167-179 页）报告称，复制体成分 Ctf4 和 Dpb3/4 的亲本组蛋白沉积可促进 TS，同时抑制容易出错的 TLS。Dpb3/4 的缺失恢复了ctf4 Δ 细胞对 DNA 损伤剂的抵抗力，但代价是由于 TLS 升高而导致诱变的协同增加。这些发现说明了复制体定向染色质维持对基因组完整性的重要性以及对 DNA 损伤性抗癌治疗的反应。