Genome Integrity & Structural Biology Laboratory, NIH/NIEHS, DHHS, Research Triangle Park, NC 27709, USA.
Currently Marta A. Garbacz works at Exact Sciences Corporation, Torrey Pines Science Park, La Jolla, CA 92037, USA.
Nucleic Acids Res. 2024 Sep 9;52(16):9574-9585. doi: 10.1093/nar/gkae616.
The endonuclease activity of Pms1 directs mismatch repair by generating a nick in the newly replicated DNA strand. Inactivating Pms2, the human homologue of yeast Pms1, increases the chances of colorectal and uterine cancers. Here we use whole genome sequencing to show that loss of this endonuclease activity, via the pms1-DE variant, results in strong mutator effects throughout the Saccharomyces cerevisiae genome. Mutation rates are strongly increased for mutations resulting from all types of single-base substitutions and for a wide variety of single- and multi-base indel mutations. Rates for these events are further increased in strains combining pms1-DE with mutator variants of each of the three major leading and lagging strand replicases. In all cases, mutation rates, spectra, biases, and context preferences are statistically indistinguishable from strains with equivalent polymerases but lacking initial mismatch recognition due to deletion of MSH2. This implies that, across the nuclear genome, strand discrimination via the Pms1 endonuclease is as important for MMR as is initial mismatch recognition by Msh2 heterodimers.
核酸内切酶 Pms1 的活性通过在新复制的 DNA 链上产生一个缺口来指导错配修复。失活酵母 Pms1 的同源物 Pms2 会增加结直肠癌和子宫癌的风险。在这里，我们使用全基因组测序表明，通过 pms1-DE 变体失去这种核酸内切酶活性会导致酿酒酵母基因组中强烈的突变体效应。所有类型的单碱基替换以及各种单碱基和多碱基缺失突变导致的突变率大大增加。在结合了 pms1-DE 与三种主要的前导链和滞后链复制酶的每个突变体的菌株中，这些事件的发生率进一步增加。在所有情况下，突变率、频谱、偏差和上下文偏好与由于 MSH2 缺失而缺乏初始错配识别的等效聚合酶菌株在统计学上无法区分。这意味着，在整个核基因组中，通过 Pms1 核酸内切酶进行的链辨别对于 MMR 与 Msh2 异二聚体的初始错配识别同样重要。
