Examining the Role of Msh2 and Mre11 in Telomere Rescue
Abstract
Instability at telomeres can result in "uncapping" of the ends of linear chromosomes, making them vulnerable to recombination, mutation and gross-chromosomal rearrangement (GCR). Continuously dividing human somatic cells and S. cerevisiae cells lacking functional telomerase experience progressive telomere degradation that culminates in replicative senescence. The disruption of telomere replication in S. cerevisiae leads to increases in deletions and mutations during replicative senescence at the CAN1 locus that is located approximately 32kb from the telomere on the left arm of chromosome V. We show that the error-prone polymerase genes RAD30, REV1 and REV7 control the stability of a telomere proximal locus, in the absence of telomere replication. We found that the absence of telomere replication led to a large increase in GCR during senescence. Furthermore, we show that REV1 and REV7 are necessary for increased GCR and mutation. Additionally, RAD30 is involved in protecting telomere proximal sequences from GCR, potentially by promoting repair by homologous recombination. Our results demonstrate that error-prone polymerases are involved in maintaining the stability of telomere proximal sequences in the absence of telomerase. This suggests that DNA replication may be disrupted in these areas of the genome. This work changes the way we view the relationship between telomere dynamics and genome stability, and how these dynamics may contribute to cancer and genome evolution.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2006
- Accession Number
- ADA452612
Entities
People
- Damon Meyer