ena-STUDY-UMCU-23-10-2014-13:00:00:388-130
Aneuploidy promotes genomic instability by impairing DNA replication
Numerical aneuploidy results in developmental defects and is common in tumors. Despite the striking association of aneuploidy with disease, molecular mechanisms explaining these effects have remained elusive. Here we show that aneuploid human cells accumulate chromosomal rearrangements with a breakpoint junction pattern suggestive of replication defects. Elevated frequency of anaphase bridges, ultrafine bridges and chromosomal gaps and constrictions as well as increased accumulation of 53BP1 foci in G1 cells provide further support that aneuploidy impairs DNA replication. Direct analysis of DNA replication on single molecules by DNA combing determined that DNA replication rate and origin licensing is impaired in aneuploid human cells. The expression of factors required for replication is significantly reduced by aneuploidy. We demonstrate that downregulation of MCM2-7, a DNA helicase required for origin licensing and DNA replication, directly contributes to the genomic instability observed in aneuploid cells. Our study demonstrates for the first time that whole chromosome aneuploidy triggers genomic instability by causing DNA replication defects and lesions at replication forks. We suggest that the chromosomal aberrations triggered by aneuploidy could contribute to tumor development.
Numerical aneuploidy results in developmental defects and is common in tumors. Despite the striking association of aneuploidy with disease, molecular mechanisms explaining these effects have remained elusive. Here we show that aneuploid human cells accumulate chromosomal rearrangements with a breakpoint junction pattern suggestive of replication defects. Elevated frequency of anaphase bridges, ultrafine bridges and chromosomal gaps and constrictions as well as increased accumulation of 53BP1 foci in G1 cells provide further support that aneuploidy impairs DNA replication. Direct analysis of DNA replication on single molecules by DNA combing determined that DNA replication rate and origin licensing is impaired in aneuploid human cells. The expression of factors required for replication is significantly reduced by aneuploidy. We demonstrate that downregulation of MCM2-7, a DNA helicase required for origin licensing and DNA replication, directly contributes to the genomic instability observed in aneuploid cells. Our study demonstrates for the first time that whole chromosome aneuploidy triggers genomic instability by causing DNA replication defects and lesions at replication forks. We suggest that the chromosomal aberrations triggered by aneuploidy could contribute to tumor development.