Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, United States of America.
Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, CA, United States of America.
PLoS Genet. 2022 Jun 13;18(6):e1010275. doi: 10.1371/journal.pgen.1010275. eCollection 2022 Jun.
Timely completion of eukaryotic genome duplication requires coordinated DNA replication initiation at multiple origins. Replication begins with the loading of the Mini-Chromosome Maintenance (MCM) complex, proceeds by the activation of the Cdc45-MCM-GINS (CMG) helicase, and ends with CMG removal after chromosomes are fully replicated. Post-translational modifications on the MCM and associated factors ensure an orderly transit of these steps. Although the mechanisms of CMG activation and removal are partially understood, regulated MCM loading is not, leaving an incomplete understanding of how DNA replication begins. Here we describe a site-specific modification of Mcm3 by the Small Ubiquitin-like MOdifier (SUMO). Mutations that prevent this modification reduce the MCM loaded at replication origins and lower CMG levels, resulting in impaired cell growth, delayed chromosomal replication, and the accumulation of gross chromosomal rearrangements (GCRs). These findings demonstrate the existence of a SUMO-dependent regulation of origin-bound MCM and show that this pathway is needed to prevent genome rearrangements.
真核生物基因组复制的及时完成需要在多个起始点协调 DNA 复制起始。复制始于 Mini-Chromosome Maintenance（MCM）复合物的加载，通过 Cdc45-MCM-GINS（CMG）解旋酶的激活进行，并且在染色体完全复制后 CMG 去除结束。MCM 和相关因子的翻译后修饰确保了这些步骤的有序进行。尽管 CMG 的激活和去除机制部分被理解，但受调控的 MCM 加载却没有，这导致对 DNA 复制如何开始的理解不完整。在这里，我们描述了 Mcm3 通过 Small Ubiquitin-like MOdifier（SUMO）的特异性修饰。阻止这种修饰的突变会减少复制起始点处加载的 MCM 并降低 CMG 水平，导致细胞生长受损、染色体复制延迟和大染色体重排（GCR）的积累。这些发现表明存在依赖 SUMO 的对起始点结合的 MCM 的调节，并且表明该途径对于防止基因组重排是必需的。
