Aska Elli-Mari, Zagidullin Bulat, Pitkänen Esa, Kauppi Liisa
Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Front Genet. 2022 Jul 8;13:913163. doi: 10.3389/fgene.2022.913163. eCollection 2022.
Microsatellite sequences are particularly prone to slippage during DNA replication, forming insertion-deletion loops that, if left unrepaired, result in mutations (expansions or contractions of the repeat array). Mismatch repair (MMR) is a critical DNA repair mechanism that corrects these insertion-deletion loops, thereby maintaining microsatellite stability. MMR deficiency gives rise to the molecular phenotype known as microsatellite instability (MSI). By sequencing MMR-proficient and -deficient ( and ) single-cell exomes from mouse T cells, we reveal here several previously unrecognized features of MSI. Specifically, mutational dynamics of insertions and deletions were different on multiple levels. Factors that associated with propensity of mononucleotide microsatellites to insertions versus deletions were: microsatellite length, nucleotide composition of the mononucleotide tract, gene length and transcriptional status, as well replication timing. Here, we show on a single-cell level that deletions - the predominant MSI type in MMR-deficient cells - are preferentially associated with longer A/T tracts, long or transcribed genes and later-replicating genes.
微卫星序列在DNA复制过程中特别容易发生滑动，形成插入缺失环，如果不进行修复，就会导致突变（重复序列阵列的扩增或收缩）。错配修复（MMR）是一种关键的DNA修复机制，可纠正这些插入缺失环，从而维持微卫星稳定性。MMR缺陷会导致一种称为微卫星不稳定性（MSI）的分子表型。通过对来自小鼠T细胞的MMR功能正常和缺陷（ 和 ）的单细胞外显子组进行测序，我们在此揭示了MSI的几个以前未被认识到的特征。具体而言，插入和缺失的突变动态在多个层面上有所不同。与单核苷酸微卫星插入与缺失倾向相关的因素包括：微卫星长度、单核苷酸序列的核苷酸组成、基因长度和转录状态，以及复制时间。在此，我们在单细胞水平上表明，缺失——MMR缺陷细胞中主要的MSI类型——优先与较长的A/T序列、长基因或转录基因以及较晚复制的基因相关。
