- Recent experiments on the nematode worm C. Elegans offer insights
into the mechanisms operating in the MMR (mismatch repair) pathway that
are key to repairing the DNA damage occurring during cell division.
- Cancer is caused by damage and alteration in the DNA, however, the precise details
of pathways operating in repair of damaged DNA (eg:
MMR to prevent cancer) remain unclear.
- Improved knowledge of the sequence of
these genetic changes or mutations taking place in the cell,
will aid in understanding the origins of cancer and may open up newer
avenues for cancer treatment.
Controlled tests on the worm model C. Elegans
delineate mechanisms operating in the mismatch repair (MMR) pathways may be
relevant to humans as well and this knowledge could pave the way for newer
approaches to cancer therapy according to a group of scientists from European Bioinformatics
Institute (EMBL-EBI), the University of Dundee and the Wellcome Sanger
results of the study appear in the journal Genome Research
Details of Study -
Nematode Worm Model to Analyze Mismatch Repair Pathway
- The study team hoped to assess in detail how the DNA repair
mechanisms operate, in particular the DNA mismatch repair (MMR)
pathway to prevent DNA
damage and therefore reduce risk of cancer.
- Previous research has shown that one of the first DNA repair pathways
affected, resulting in increased risk of cancer is DNA mismatch repair
- The team proceeded to analyze the MMR
pathway in greater detail using the nematode worm model C. Elegans.
- What makes the nematode worm the
model of choice is that it requires
only three days for these worms to be propagated from one generation to
the next, greatly expediting the process of analyzing how DNA
alterations are passed on from one generation to the next.
DNA mutations we see in cancer cells were caused
by a yin and yang of DNA damage and repair
," explains Moritz Gerstung,
Research Group Leader at EMBL-EBI.
‘Similar DNA mutational processes take place in nematodes and humans and studying the nematode worm will help in providing more insight into the origins of cancer.’
we study a patient's cancer genome
we're looking at the final outcome of multiple mutational processes that often
go on for decades before the disease manifests itself. The reconstruction of these processes and their contributions to cancer
is a bit like the forensic analysis of a plane crash site,
trying to piece together what's happened. Unfortunately, there's no black box
to help us. Controlled experiments in model organisms can be used to mimic some
of the processes thought to operate on cancer genomes and to establish their
- The team found that DNA mismatch
repair was passed down for many generations (in worms) and this enabled
them to determine a distinct mutational pattern.
Can DNA Changes In
Nematode Worm Apply to Humans?
- The million dollar question that
begged to be answered now was, whether the same processes operated
in humans as well.
- To answer this question, EMBL-EBI
PhD student Nadia Volkova compared
theC. Elegans findings
with molecular data from 500 human cancer
found a resemblance between the most common signature associated with mutations
in MMR genes in humans and the patterns found in nematode worms," explains
Volkova. This suggests that the
same mutational process operates
in nematodes and humans.
findings of the study could, therefore aid in better understanding of the processes
involved in carcinogenesis and create fresh research opportunities to develop
DNA Damage and Inbuilt
Repair Mechanisms to Prevent Cancer
Cancer is caused by genetic changes or DNA mutations
triggered by a range of external
factors such as exposure to UV radiation,
certain chemicals and smoking. However, errors occurring during the course of
cell division also are known to play an important role in carcinogenesis. A
cell recognizes most of these errors and corrects them through various repair
DNA repair is not a perfect process, so it could still leave certain mutations
unrepaired or repair them inaccurately leading to persisting changes in DNA.
the sequential changes of these mutational processes is key in identifying the
reasons for cancer and showing the way for potential avenues for new treatments.
DNA Mismatch Repair and
Mismatch Repair Deficiency
mismatch repair, errors (base mismatching) that occur during
DNA replication are recognized, removed and replaced
. The mismatch repair
pathway maintains the stability
the genome during repeated cell division.
MLH1, MSH2, MSH6 and PMS2 genes are involved in the process of "mismatch
or MMR. In persons with constitutional mismatch
innate repairing process is affected
. Such children are more prone to develop
gastrointestinal polyps, lymphomas, hematological cancers and rare childhood
such as these show the way for further research into these pathways, details of
involved and how to address defective repair pathways.
- Constitutional Mismatch Repair Deficiency Syndrome - (https://www.stjude.org/disease/constitutional-mismatch-repair-deficiency.html)