Telomere Damage and Cancer
Natural chromosome ends are capped by specialized nucleoprotein
structures called telomeres. Telomeres are essential for the
maintenance of genome integrity by protecting natural chromosome
ends from being seen and treated as broken DNA ends. Telomeres
consist of tandem TTAGGG DNA repeat sequences bound by the
'shelterin' complex of telomere-specific proteins that control the
length and end-protection function of telomeres. Chromosome ends
can lose telomere protection when telomeres become critically short
as a consequence of multiple rounds of cell division and when the
activity of shelterin components is lost.
When telomeres become dysfunctional they limit the replicative
lifespan of a cell by activating a DNA damage response that forces
it into a senescent state or to undergo cell death (apoptosis).
While these both contribute to the aging process, they also act as
a mechanism to inhibit cancer development by limiting the outgrowth
of incipient cancer cells. However, if the cell escapes senescence
or death and divides, misplaced DNA repair at chromosome ends
causes end-to-end chromosomal fusions that can lead to extensive
genome instability and ultimately to cancer.
The aim of our work is to understand the molecular mechanisms
that underlie these responses to telomere dysfunction and that have
critical consequences for cancer development and aging. To do this,
we take both unbiased and candidate-driven approaches, alongside
in-depth mechanistic studies, particularly focused on identifying
what precise DNA damage signaling responses and processing
activities act at telomeres and how these are regulated.
We are utilizing genetic screens and proteomics-based approaches
to identify proteins and post-translational modifications with
critical roles in the cellular response to unprotected telomeres.
We use well-controllable models such as the fast and reversible
temperature-dependent inactivation of the telomere-capping protein
TRF2, which allows us to investigate both immediate and late events
associated with the activation of DNA damage responses at
telomeres. These models also allow us to address how DNA damage
responses are inhibited or terminated. Through subsequent
functional studies on the newly identified factors and pathways, we
aim to generate a comprehensive understanding of the mechanisms
underlying telomere-dependent control of cancer development and