How does the germline achieve immortality?

The germline is an immortal cell lineage that is passed from one generation to the next, indefinitely. Very little has been done to addess the problem of germline immortality experimentally. In order to determine how the germline achieves immortality, I decided to look for C. elegans mutants with mortal germlines - mutants which could grow for several healthly generations but eventually became sterile (ie, their germlines accumulate some kind of damage which eventually results in sterility). There are probably 50 to 100 genes which can mutate to give a Mortal Germline phenotype (Figure 1).

Figure 1. mortal germline mutants eventually become sterile.

We would like to understand the protective mechanisms which ensure that the germline achieves youth, vigor and immortality. Pathways that protect C. elegans germline cells against damage should be broadly relevant to the human problems of cancer and aging, which occur as a result of cellular damage.

How are telomeres replicated?

Telomeres, the ends of linear chromosomes, are usually composed of simple repetitive sequences. In most organisms, telomere length is maintained by an enzyme called telomerase, which adds repeats to the ends of chromosomes. Studies in yeast and other organisms have identified a number of genes that are required for telomere replication. About 10% of mortal germline mutants described above appear to be completely defective for telomerase (Figure 2). One of these telomerase-defective mutants, mortal germline-2, has been cloned and encodes a DNA damage checkpoint gene, which suggests that telomeres may be identified as a special kind of DNA damage prior to telomere replication. We plan to identify and study more genes that are required for telomere replication inC. elegans - this small nematode has the advantage of being the most highly evolved multicellular eukaryote (ie, closest to humans) in which an unbiased genetic approach can be used to study the problem of telomere replication.

Figure 2. Telomere replication defects such as (a) telomere shortening and (b) end-to-end chromosome fusions are observed in a subset of mortal germline mutants, suggesting that telomerase does not function properly in these mutants.

How is DNA damage detected and repaired?

We are interested in proteins that detect or repair DNA damage, and in how such proteins might affect telomere replication.