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Why do DNA mutations matter?

Dr Alex Jeffries and Dr Chris Todd

iStock © BlackJack3D
Cancer and mutations
Cancer is a genetic disease because it is caused by mutations
in the genetic material of cells
It originates within the cells themselves

Typically the cells affected are the normal cells that make up
the body of an organism (called somatic cells)

Rarely are the reproductive cells affected (called germ-line


cells)

To understand why mutations matter, we have to know a bit


about normal versus aberrant cellular function
The genome
With a few exceptions, all cells contain a complete copy of
that organism’s genome

The genome is the total information needed for the physical


form and function of a whole organism
An analogy
You could liken the genome to a complete encyclopedia that
defines all aspects of an organism

Each volume of the encyclopedia is like a chromosome

Each entry in a volume is like a gene

© Pepo13
How the genome is expressed
In any given cell, only a subset of the genome will be used
Typically described as being “expressed”

What makes the cell what it is and what it does is largely


determined by;
The subset of proteins it expresses
How much of each protein is made
When each protein is made
A cell is a complex and dynamic system
Each type of cell is a specific combination of these expression
characteristics

There are dynamic interactions between expression


characteristics
This leads to an enormously complex system
Cell function is a balancing act
Some perturbations of the system can be tolerated

Too much perturbation can lead to either cell death or aberrant


cellular function

Mutations are one type of perturbation


DNA replication
Every time a cell divides, it has to replicate
its DNA

A parental DNA template is used to make a


copy

© I, Madprime
Mutations
Errors can occur during the replication process itself
ie the template is correct but the replication enzymes make
an error

Errors can occur because the DNA template has been damaged
ie the replication enzymes make no errors, but what they
copy is an error

Errors can occur when the chromosomes are being segregated


Mutation repair
There are a number of error-correction mechanisms in cells

The replication enzymes can check what they are making

Repair enzymes constantly monitor DNA to identify and correct


errors

Despite these repair systems, errors sometimes get through


and are passed on to subsequence daughter cells
Mutations are passed on and accumulate

Adapted from Alison, M (2001) Cancer.


DOI: 10.1038/npg.els.0001471
Categories of mutations
A single nucleotide base is substituted for a different one

A T G T G G A C C G T C

A T G T G A A C C G T C
Categories of mutations
One or more nucleotide bases are deleted from the DNA

A T G T G G A C C G T C

A T G T G A C C G T C
Categories of mutations
One or more nucleotide bases are inserted into the DNA

A T G T G G A C C G T C

A T G T G T G A C C G T C
Categories of mutations
A section of DNA is moved from one location to another
(translocated)

A T G T G G A C C G T C

T G G A C C G T C A T G
Categories of mutations
Translocation may involve making a copy of the DNA section
(duplication)

A T G T G G A C C G T C

A T G T G G A C C G T C A T G
Categories of mutations
A section of DNA is flipped over (inverted)

A T G T G G A C C G T C

A T G T C C A G G G T C
Categories of mutation effects
Stopping protein production X
Changing identity of a protein
Might stop protein function X
Might change protein function

Changing quantity of a protein

Changing timing of protein production

Knock-on effects
The cellular effects of mutations
Nothing happens

Death of the cell

Aberrant cellular function which is passed on to subsequent


daughter cells

One subset of aberrant cellular behaviour is cancer


Uncontrolled growth and spread of cells
More mutations means more chance of
cancer
Cancers rarely arise from a single mutation in a single gene

Typically multiple genes, up to 10 or so, must all be mutated in


order for a cell to become cancerous

Certain genes are more prone to causing cancer if mutated


eg DNA repair enzymes

Thus, the more mutations a given cell line experiences, the


more likely it will accumulate sufficient to result in cancer
Mutations are passed on and accumulate

Adapted from Alison, M (2001) Cancer.


DOI: 10.1038/npg.els.0001471
Mutations matter
Part of the future of cancer research lies in;
Identifying which genes and groupings of genes are more
likely to result in cancer if they are mutated

What types of mutations are more likely to result in cancer

Can we develop treatments for cancer if we understand the


molecular underpinnings of cancer?
Distributed by UNIVERSITY OF BATH and FUTURELEARN under licence

Acknowledgements
Academic content for Inside Cancer:
© Dr Momna Hejmadi (Lead Educator), Dr Lorenzo Caggiano, Dr Jim Caunt, Dr Andrew
Chalmers, Professor Laurence Hurst, Dr Alex Jeffries, Dr Julien Licchesi, Dr Adele
Murrell, Dr Chris Todd, Professor David Tosh, Dr Andrew Ward 2014

Production:
© University of Bath 2014

Images:
© Alison, M (2001) Cancer. DOI 10.1038/npg.els.0001471
© I, Madprime [CCO, GLDL (http://www.gnu.org/copyleft/fdl.html), CC-BY-SA-3.0
© Pepo13 (Own work) [CC-BY-SA-3.0, via Wikimedia Commons]

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