O
ur genomes aresubjected to a plethora of
potentially damaging insults over the course
of our lifetimes. Oxidative damage, irradia-
tion, chemicals, and errors that occur when
the genome is copied during cell division can
lead to nicks, breaks and other damage to DNA.
Cells have evolved various “sensor” molecules to respond to
this DNA damage, leading to either repair of the damage or
cellular “suicide” if the damage cannot be repaired. This is an
important safeguard that helps to prevent our normal cells
from becoming cancerous.
In cancer cells, however, these responses to DNA damage are
often defective, leading to the accumulation of mutations that
can promote cancer cell division. We now know that cancer
cells have yet another trick up their sleeve – they can also exploit
these DNA damage-signalling molecules to keep the ends of
their chromosomes long, essentially endowing themselves with
immortal life.
The aspect of cell biology that has most fascinated me for the
past 20 years is the process by which normal cells sense the fact
that they are ageing. The ends of our chromosomes, known as
“telomeres”, gradually shorten with each cell division over time.
This process acts like an elegant biological “clock” that tells the
cells of our body to age.
However, cancer cells counteract this clock and keep growing
out of control. They use an enzyme called telomerase to reset
the timer over and over again by adding telomeric DNA to the
ends of chromosomes.
Telomerase was irst discovered in 1985 by Australian scien-
tist Elizabeth Blackburn and her graduate student Carol Greider
in their laboratory at the University of California. They were
awarded the Nobel Prize for this discovery in 2009. Interestingly,
their initial discovery did not involve cancer cells or even human
cells – they discovered telomerase in a single-celled pond organism.It was found almost a decade later that most cancer ce use an iden-
tical process tokeep dividing indeinitely.
The research in my laboratory at Children’s Medical Research
Institute is directed at understanding more about how telom-
erase works so that ultimately we can devise ways of blocking
it as a future cancer therapy. One of the questions we have been
addressing in recent years is to ask how telomerase gets to where
it needs to go in the cell – the telomere.
It turns out that this is an incredibly complex process, but
we have been able to get a handle on the problem by intro-
ducing a luorescently labelled DNA probe into the cells. This
probe is designed to seek out telomeres, where it can be visu-
alised as luorescently coloured dots under a microscope. We
then introduce another probe that’s labelled with a different
luorescent colour. This second probe recognises telomerase.
When we see overlapping dots of the two colours, we know
that telomerase has reached the telomere (Fig. 1). These events
can then be quantiied.
Two key DNA damage-signalling proteins that are widely
conserved throughout evolution are known as ATM and ATR.
These proteins are necessary for telomerase to reach telomeres
in yeast, but there were conlicting results regarding their involve-
ment in this process in mammalian cells.
In experiments started by PhD student Josh Stern in our
lab, we found that ATM is indeed necessary for telomerase to
reach the telomeres in human cells. When Josh depleted the
amount of ATM in cells, the overlapping dots representing
telomerase dramatically disappeared from the telomere.
This was an exciting inding, but Josh was about to wrap up
his PhD studies and head to the USA for postdoctoral work so
another student, Adrian Tong, took over the project. Adrian
carried out an enormous amount of experimental work over
the course of his PhD, and was successful in iguring out many
of the molecular details of this process.30 | JUNE 2016bj tdt lth f It f dl t d dlt tht t l idMortality
Molecules
TRACY BRYAN
Cancer cells become immortal by exploiting a mechanism
that protects normal cells from DNA damage. Can we useSvislo/istockphoto these molecules to turn off cancer’s fountain of youth?