Telomeres in cancer and ageing paper

2015-01-13

Telomeres in cancer and ageing

review paper
royal society paper

"C:\Users\kurtw_000\Box Sync\DocDR\2014\02-04-2014d0911\Telomeres in cancer and ageing paper.pdf"

Abstract
Telomeres protect the chromosome ends from unscheduled DNA repair and degradation.
Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound
to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-
binding proteins are both important for telomere protection. Furthermore, telomere length and
integrity are regulated by a number of epigenetic modifications, thus pointing to higher order con-
trol of telomere function. In this regard, we have recently discovered that telomeres are transcribed
generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are
likely to have important roles in telomere regulation. In the past, we showed that telomere length
and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of
stem cells. These effects of telomerase and telomere length on stem cell behaviour anticipate the
premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demon-
strated the anti-ageing activity of telomerase by forcing telomerase expression in mice with
augmented cancer resistance. Shelterin is the major protein complex bound to mammalian telo-
meres; however, its potential relevance for cancer and ageing remained unaddressed to date. To
this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1
and Rap1. The study of these mice demonstrates that telomere dysfunction, even if telomeres are
of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromo-
somal aberrations and initiation of neoplastic lesions. These new mouse models, together with
the telomerase-deficient mouse model, are valuable tools for understanding human pathologies
produced by telomere dysfunction

Some notes

we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1

and Rap1.

telomerase deficient mice do live shorter lives even during the 1st generation
To counterbalance this undesired

effect of telomerase over-expression, we over-
expressed telomerase in the context of cancer-resistant
mice having increased levels of the tumour suppressors
p53, p16 and p19ARF (SUPER-M mice; ?gure 3)

These results indicate that the

anti-ageing activity of Tert requires telomerase catalytic
activity, which strongly implicates telomere mainten-
ance as the main mechanism underlying the
longevity enhancing effect of telomerase expression

TELOMERE REJUVENATION DURING THE

GENERATION OF INDUCED PLURIPOTENT
STEM CELLS

cartoon of mice with premature aging less cancer, less ageing more cancer, and SUPER-M mice with less
p53 IS A KEY FACTOR LIMITING

REPROGRAMMING OF SUBOPTIMAL CELLS
aging
-THE IMPORTANCE FOR CANCER AND AGEING
OF CANCELLING THE DNA DAMAGE RESPONSE
AT CHROMOSOME ENDS

MOUSE MODELS FOR CONDITIONALLY

DELETED SHELTERIN PROTEINS

another cartoon with some nice mice
last section: TELOMERES AND LONGEVITY
major cause of mouse ageing since telomere

shortening produces defects in the regenerative
capacity of tissues

Thus, telomere uncapping, even in the presence

of normal length telomeres, is capable of inducing
age-related pathologies in young mice