ATM is a type of protein known as a “kinase”, and its func-
tion is to add a phosphate molecule to other proteins. This
phosphate can then change the function of the protein it is
attached to. Adrian’s irst task was to determine which protein
was receiving a phosphate from ATM during the process of
telomerase recruitment to the telomere.
A good candidate was the protein TRF1, an integral struc-
tural component of telomeres. The laboratory of Prof Xu-Dong
Zhu at McMaster University in Canada had already shown
that ATM was able to add a phosphate to TRF1. Adrian collab-
orated with Prof Zhu’s lab and showed that this was the key
event in telomerase recruitment. When ATM adds a phos-
phate to TRF1, this causes TRF1 to fall off the telomere, which
in turn allows telomerase access to the telomere.
TRF1 is not normally used by ATM to respond to other
types of DNA damage, so cancer cells are stacking the odds in
their favour by exploiting the way that normal cells protect
themselves against DNA damage, and using it to turn themselves
immortal.
In other experiments, Adrian discovered that ATR, a close
relative of ATM, is also involved in telomerase recruitment
but in a different way. ATR responds to problems that occur
during the process of DNA copying; one of its functions is to
detect when there are “road blocks” interfering with the DNA
replication machinery.
We found that if road blocks occur during the copying of
telomeres, ATR reacts by bringing telomerase to telomeres.
We speculate that this signal ensures that telomerase is brought
to the telomere immediately after it has been replicated. This
is therefore a second way that cancer cells are using a normal
cellular response to DNA damage to ensure that their telom-
eres remain long.
These indings had the potential to be controversial, given
the previous contradictory data between yeast and mammalian
cells. We were therefore thrilled to learn that, using a different
and complementary technique, the laboratory of Carol Greider,
now a Professor at Johns Hopkins University, had also found
that ATM is necessary for human telomerase to elongate telom-
eres. Both studies were recently published back-to-back in the
journal Cell Reports (http://tinyurl.com/z87oy3w).
A majority of human cancers rely on telomerase for their
continued growth. The new indings mean that new cancer
treatments under development, some aimed at impairing telom-
erase function and others aimed at ATM, might show an even
greater anti-cancer effect if they are used together. We are
currently testing this possibility.
But cancer cells are not the only human cells that need telom-
erase. Most of the cells in an adult human body do not contain
detectable amounts of telomerase, but it is relatively abundant
in egg and sperm cells and in embryonic tissues in order to
“reset” telomere length for the next generation. It’s likely that
ATM is also required to recruit telomerase to telomeres in
these cells, which partly explains the observation of short telom-
eres in the ATM-deicient cells of ataxia telangiectasia patients,
who have impaired brain function, signs of premature ageing,
and increased risk of certain types of cancers.
It’s likely that more surprises are in store as we and others
unravel the complex links between telomere maintenance and
the protection of the rest of the genome. This is likely to increase
our understanding of the process of ageing, as well as how cancer
cells subvert this process to achieve immortality.
A/Prof Tracy Bryan is Unit Head of the Cell Biology Unit at the Children’s Medical Research
Institute.JUNE 2016|| 31Figure 1. Measuring the presence of telomerase at telomeres inside human cells. The nucleus of a single cell is
outlined in white. A probe labelled with a red fluorescent dye shows the location of telomeres, while a green
fluorescent probe indicates the presence of telomerase. Overlapping red and green dots appear as yellow dots
in the merged image, providing direct visualisation of the presence of telomerase at the telomeres.Image: Melissa Kartawinata, CMRIThe new findings mean that new
cancer treatments under
development... might show an even
greater anti-cancer effect if they are
used together.