Chromosomal rearrangements associated with SMC5/6 deficiency in DNA replication

Genes Cells. 2024 Dec;29(12):1251-1263. doi: 10.1111/gtc.13180. Epub 2024 Nov 14.

Abstract

Completion of DNA replication before chromosome segregation is essential for the stable maintenance of the genome. Under replication stress, DNA synthesis may persist beyond S phase, especially in genomic regions that are difficult to proceed with the replication processes. Incomplete replication in mitosis emerges as non-disjoined segment in mitotic chromosomes leading to anaphase bridges. The resulting chromosome rearrangements are not well characterized, however. Here, we report that incomplete replication due to SMC5/6 deficiency impairs sister chromatid disjunction at difficult-to-replicate regions, including common fragile sites. These non-disjoined regions manifest as cytologically defined symmetric gaps, causing anaphase bridges. These bridges break at the gaps, leading to telomere loss, micronucleation, and fragmentation. Subsequently, fusions between telomere-deficient chromosomes generate complex chromosomal rearrangements, including dicentric chromosomes, suggesting the occurrence of breakage-fusion-bridge cycle. Additionally, chromosomes in micronuclei were pulverized, indicative of chromothripsis. Our findings suggest that incomplete replication facilitates complex chromosomal rearrangements, which may contribute to genomic instability in human cancers.

Keywords: SMC5/6; anaphase bridge; breakage‐fusion‐bridge cycle; chromothripsis; common fragile sites.

MeSH terms

  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Chromatids / genetics
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Aberrations
  • Chromosome Fragile Sites / genetics
  • Chromosome Segregation
  • DNA Replication* / genetics
  • Genomic Instability
  • Humans
  • Mitosis / genetics
  • Telomere / genetics
  • Telomere / metabolism

Substances

  • Cell Cycle Proteins
  • SMC5 protein, human
  • SMC6 protein, human
  • Chromosomal Proteins, Non-Histone