Brian D. Bower
The t-loop model proposed in our laboratory by Dr. Griffith was based
on the long history of this laboratory on recA driven recombination
and is supported by a large and growing body of research. However,
despite the advances of the last decade, the mechanism underlying
t-loop formation remains poorly understood. While the shelterin factor
TRF2 has been shown to promote t-loop formation in vitro, it remains
unknown to what degree TRF2 and the other shelterin factors are
necessary in vivo. Indeed seems unlikely that TRF2 alone is sufficient
to catalyze t-loop formation in vivo given the presence of nucleosomes
and an intact shelterin complex in a physiological context.
It is reasonable to assume that the process of t-loop formation is
driven by homologous recombination machinery, as the process of
telomere maturation and capping occur during and immediately following
S-Phase; a time when HR proteins are at relatively high concentration.
Indeed, this notion is supported in part by the observation that BRCA2
recruits Rad51 to telomeres in a cell-cycle specific manner, and that
disruption of this process results in telomere erosion and dysfunction.
However, it remains unclear whether this erosion and dysfunction are due
to a capping deficiency (e.g. failure to form a t-loop) or due to
replication stress (i.e. failure to resolve stalled replication forks).
Using a variety of techniques and several reagents from our collaborators
I am working to determine whether a mixture of factors including BRCA2
and Rad51 are able to produce t-loops in model telomeres in the presence
of a variety of shelterin components and other proteins.