The long-term objective of this work is to understand the mechanisms that organisms use to ensure that genome integrity is maintained from generation to generation and from cell to cell. Genomes are subject to damage in a variety of forms and have evolved a variety of mechanisms to repair damage, or to cope with failure. To maintain chromosome stability, the linear chromosomes of eukaryotes must be capped with telomeres. Loss of a single telomere is a particularly challenging form of genome damage, and most often results in apoptosis, rather than successful repair. Two forms of repair are known for this type of damage: healing, which refers to the addition of a new telomere on the non-telomeric end of a chromosome; or Break-Induced Replication (BIR), in which the broken chromosome copies information from another chromosome to replace the end that it is missing. Both types of repair are associated with alterations in the genome. Since this is generally undesirable, these modes of repair may be considered repair of last resort. The work proposed here will investigate the germline responses to telomere loss. The goals are to identify the genetic controls that are used to detect and eliminate cells with this form of damage. Differences in the responses between male and female germlines will be explored. The experiments proposed here will also investigate the BIR mode of repair, which has not been previously demonstrated in any germline. This type of repair has additional interest because of its similarity to a form of telomere maintenance found in some cancer cells.
When damaged chromosomes are passed from parent to offspring, they may cause developmental disorders. When chromosome damage occurs during development, it may lead to cancer. This work investigates the mechanisms that are used to prevent the transmission of damaged chromosomes.
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