Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes Dev. 2022 Feb 1;36(3-4):103-105. doi: 10.1101/gad.349408.122.
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 , 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 Δ 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.
基因组 DNA 不断受到内源性和外源性损伤源的挑战。由此产生的损伤可能成为 DNA 复制的物理障碍，需要修复机制与 DNA 复制体机械内在偶联。DNA 损伤容忍 (DDT) 包括跨损伤合成 (TLS) 和模板切换 (TS) 修复过程，使复制体能够绕过体积较大的 DNA 损伤并完成 DNA 复制。复制体如何协调 DDT 修复机制在复制障碍处变得活跃仍然是一个谜。在本期的 中，Dolce 及其同事（第 167-179 页）报告说，由复制体成分 Ctf4 和 Dpb3/4 进行亲本组蛋白沉积促进了 TS，同时抑制了易错的 TLS。在 Δ 细胞中，缺失 Dpb3/4 以牺牲协同增加的突变率为代价，恢复了对 DNA 损伤剂的抗性，这是由于 TLS 升高所致。这些发现说明了复制体定向染色质维持对基因组完整性和对 DNA 损伤性抗癌治疗的反应的重要性。
