My
laboratory is interested in germline immortality, in telomere
replication, in DNA damage. We are studying these problems
using the nematode Caenorhabditis elegans, which is a higher
eukaryote with very good genetics.
How
does the germline achieve immortality? The germline is an immortal
cell lineage that is passed from one generation to the next,
indefinitely. 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 healthy
generations but eventually became sterile (i.e., 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.
A
large-scale genetic screen for mortal germline mutants is underway.
These mutants will be sorted into categories by conducting
a series of tests to determine how their germlines are being
damaged. Eventually, we hope 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, telomeres are maintained by an enzyme called telomerase,
which adds repeats to the ends of a chromosome. Studies in
yeast have identified a number of proteins that are required
for telomere replication. About 10% of mortal germline mutants
described above are defective for the enzyme telomerase. One
of these telomerase-defective mutants, mortal germline-2, has
been cloned and encodes a DNA damage checkpoint gene, which
was surprising since mutations in this gene do not completely
eliminate telomere replication in yeast. Thus, we may learn
new things about telomeres by studying them in a higher eukaryote
like C. elegans. We hope to identify more C. elegans genes
that are required for telomere replication.
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.
