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FEATURE ARTICLE
BIJU DHARMAPALAN
E
VERY individual’s life is determined
by their DNA spanning the 23 pairs
of chromosomes. How an organism
would look like or how an organism
would function is written in these novel
molecules made of four nucleotides. They
are indeed the blueprint of life and get
copied (replicated) several times within
the life span of an organism.
Any change in the nitrogen bases
adversely affects the gene expression.
Every day our DNA is exposed to many
Tomas did postdoc
with Jacques Fresco at
Princeton, to work on
heat-induced unfolding of
transfer RNA. Experiments
showed that even under
normal conditions DNA
quickly suffered enough
damage to make life
impossible. Lindahl began
to search for enzymes that
might repair this unseen
damage.
SCIENCE REPORTER, DECEMBER 2015
adverse situations. It may be damaged
by UV radiation, free radicals and other
carcinogenic substances. The DNA is also
prone to certain spontaneous mutations
that are inherent making it highly
unstable.
The inherent instability of DNA
constitutes both an opportunity and a
threat. DNA lesions can block important
cellular processes such as DNA
replication and transcription, cause
genome instability and impair gene
expression. Lesions can also be mutagenic
and change the coding capacity of the
genome, which can lead to devastating
DNA – the blueprint of life
(Photo credit: www.astrochem.org)
Prof. Tomas Lindahl (Photo credit: http://www.standard.co.uk)
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FEATURE ARTICLE
Aziz Sancar has mapped
nucleotide excision repair,
the mechanism that cells
use to repair UV damage
to DNA. People born with
defects in this repair system
will develop skin cancer
if they are exposed to
sunlight.
diseases and conditions associated with
genome instability, including cancer,
neurodegenerative
disorders
and
biological ageing.
At the same time, without mutations
Darwinian evolution would not be
possible. Thousands of spontaneous
changes to a cell’s genome occur on a
daily basis and defects can also arise when
DNA is copied during cell division – a
process that occurs several million times
every day in the human body. However,
those mistakes don’t turn us into X-Men
or Superwomen. The reason our genetic
material does not disintegrate into
complete chemical chaos is that a host of
proteins that work as a ‘molecular repair
kit’ continuously monitor the process and
repair DNA.
Furthermore, mutagenic chemicals
and radiation can also have a healing
effect; they can for instance, be used to
treat cancer, by introducing DNA lesions
that halt cell proliferation and stimulate
programmed cell death. The cell has
developed ways to counteract DNA
lesions and to keep DNA mutations at a
tolerable level. Life has survived through
the ages because enzymes inside every
cell ensure that the DNA remains in
proper working order.
A number of different DNA repair
mechanisms correct lesions and safeguard
the integrity of the genome. The 2015
Nobel Prize in Chemistry has been
awarded to three scientists who mapped
how cells repair damaged DNA. Tomas
Lindahl, Aziz Sancar and Paul Modrich
shared the prize, announced on 7 October
2015.
Working separately, the laureates
broke new ground by mapping and
explaining several of the ways a cell
repairs its DNA. Each discovered a
different molecular process. Lindahl
described how enzymes seek, cut out
and patch up sections of damaged DNA,
a mechanism called base-excision repair.
Sancar contributed research on the
nucleotide-excision repair system, which
explains how cells use enzymes to repair
damage caused by ultraviolet light. And
Modrich worked on mismatch repair,
which sorts out errors that are introduced
when DNA is copied.
Prof. Tomas Lindahl, Emeritus
group leader at the Francis Crick Institute,
Hertfordshire, and Emeritus director of
Clare Hall Laboratory, Hertfordshire,
both UK, trained as a medic but was lured
into research by Einar Hammarsten,
Emeritus Professor of Biochemistry at the
Karolinska Institute and an influential
pioneer in nucleic acid research.
In the mid-1960s, Tomas left Sweden
for a postdoc with Jacques Fresco at
Princeton, to work on heat-induced
unfolding of transfer RNA. Samples of
RNA in his experiments rapidly degraded
when heated. Further experiments
showed that even under normal
conditions DNA quickly suffered enough
damage to make life impossible.
Lindahl began to search for enzymes
that might repair this unseen damage.
Among other things, he studied a
malfunction in which a part of the
nucleotide cytosine—one of the four
bases that make up DNA—degrades
at everyday temperatures. When the
DNA molecule replicates, this damaged
base matches up with the wrong kind of
nucleotide, thus introducing errors into
the genetic code. Lindahl discovered a
process, now called base excision repair,
in which enzymes continually spot and
replace such interloper bases. He and
colleagues described the mechanism in
1974.
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Prof. Aziz Sancar (Photo credit: http://cdn.newsapi.
com.au)
Uracil is detected and chopped out
of the DNA chain by a glycosylase, an
enzyme able to cleave the bond between
the errant base and the backbone, leaving
the double-stranded backbone intact.
A gang of other enzymes then takes
over, chopping out the sad remains of
the original nucleotide together with its
nearest neighbours, mending the gap
using the opposite strand as a template,
and finally stitching up the break.
Prof. Aziz Sancar is the Sarah Graham
Kenan Professor of Biochemistry at the
University of North Carolina, Chapel
Hill, NC, USA. Born in 1946 to illiterate
parents at Savur, Turkey, Sancar studied
at the İstanbul University of Turkey. He
was practicing as a doctor in the Turkish
countryside till 1971 when he decided to
study biochemistry.
During his doctoral research (197477) at the University of Texas, Dallas,
he cloned the gene for photolyase, an
enzyme that helps bacteria fix damage
from otherwise lethal doses of UV light.
Later, while working as a lab technician at
Yale University School of Medicine (197782), Sancar uncovered another repair
mechanism, nucleotide excision repair,
which allows cells to fix a different kind
of damage from the one Lindahl studied,
using different enzymes.
Aziz Sancar has mapped nucleotide
excision repair, the mechanism that cells
use to repair UV damage to DNA. People
born with defects in this repair system will
develop skin cancer if they are exposed to
sunlight. The cell also utilises nucleotide
excision repair to correct defects caused
by mutagenic substances, among other
things.
SCIENCE REPORTER, DECEMBER 2015
FEATURE ARTICLE
Prof. Paul Modrich (Photo credit: http://today.duke.edu/)
Prof. Paul Modrich tackled a third
source of error: mistakes that happen
during replication, when the two strands
of DNA unzip and are copied. Currently,
he is Investigator at the Howard Hughes
Medical Institute, Durham, NC, and
James B. Duke Professor of Biochemistry
at Duke University School of Medicine,
Durham, NC, both USA.
Growing up in a small town in
northern New Mexico instilled Modrich
with a love of the natural world. His
father, the local high school biology
teacher, encouraged his curiosity. In 1963,
when he was a junior in high school,
Modrich remembers his dad giving him
very important advice: “You should learn
about this DNA stuff.” Modrich heeded
this counsel.
For most of his career, he has studied
how organisms prevent the occurrence
of mutations in their genetic material.
Modrich’s experience with DNA and
the proteins and enzymes that interact
with the molecule allowed him in the late
1970s to start tackling a system that finds
and fixes the very rare mismatched base
pairs that result from DNA polymerase
errors. Eventually, Modrich developed
biochemical assays that allowed detection
of mismatch repair (MMR System), a key
proofreading mechanism that cells use
to eliminate rare errors from DNA that
occur during chromosome replication, in
the extracts of E. coli, which permitted his
lab to identify the nature and functions
of 11 proteins responsible for mismatch
repair in this microbe.
SCIENCE REPORTER, DECEMBER 2015
Enzymes efficiently fix these errors—
and Modrich helped figure out how it
happens. In the late 1970s, he was studying
an enzyme called Dam methylase, which
dots DNA with side chains made of
carbon and hydrogen atoms, called
methyl groups. Modrich’s experiments
proved that so-called restriction enzymes
use these methyl groups as guidemarks
for cutting DNA.
Modrich showed how the MMR
system functions as a copyeditor to correct
the rare errors left by DNA polymerase.
Later, in 1990, his group showed that
the MMR system operates in human
cells also. In human cells, MMR reduces
the error rate by a factor of a thousand.
Without MMR, this number increases to
about 1,000. He showed that this reaction
is defective in a common form of colon
cancer that runs in families and identified
a number of proteins that participate in
human MMR. Since then, he and other
researchers have found that genetic
inactivation of any of four human MMR
genes can lead to cancer. Physicians now
use these findings in cancer diagnosis.
The pioneering work of these three
scientists has opened a dazzling frontier
in medicine by unveiling how the body
repairs DNA mutations that can cause
sickness and contribute to ageing. Because
DNA damage leads to notable ill effects
in humans – the side effects of old age,
certain congenital defects, and cancer,
just to name a few – understanding
these mechanisms is more than just basic
science.
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Modrich showed how the
MMR system functions as
a copyeditor to correct the
rare errors left by DNA
polymerase.
Later, in 1990, his group
showed that the MMR
system operates in human
cells also. In human
cells, MMR reduces the
error rate by a factor of a
thousand. Without MMR,
this number increases to
about 1,000.
With the work of the 2015 laureates,
researchers can work to find ways to
make our own DNA repair mechanisms.
If there’s ever a “cure” for old age, these
scientists will likely be able to take some
of the credit.
Some of the most powerful ideas in
science are the result of crosspollination
of interdisciplinary approaches that bring
together different fields to reach a greater
understanding of key problems. There is
no better example of this than the work
of this year’s Chemistry Nobel Laureates
Tomas Lindahl, Paul Modrich, and Aziz
Sancar, whose mechanistic studies of
DNA repair provided fundamental
knowledge of how a living cell functions
and can be used for the development of
new cancer treatments. The work also
puts onus on the importance of basic
research.
As Modrich has rightly put , “Basic
research often leads to unanticipated
results that ultimately have value for
human health and disease. Had we
not had a basic knowledge of MMR in
bacteria, we wouldn’t have guessed that
defects in the human pathway were the
cause of hereditary colon cancer. That
is why curiosity-based research is so
important. You never know where it is
going to lead….”
Mr. Biju Dharmapalan is Head of the Department,
School of Biosciences, Mar Athanasios College
for Advanced Studies Tiruvalla (MACFAST),
Kerala-689101; E-mail: [email protected]/biju_
[email protected]