Re: How is DNA better suited than RNA to carry genetic info?

To whom it may concern,

The question was, how is DNA better suited than RNA to carry genetic 
information.  Unfortunately, this is almost a philosophical question, since 
there really is no way of knowing for certain how the roles of DNA and RNA 
evolved.  There may not BE an answer.  Our evolutionary description of the 
role of DNA and RNA in biology comes from a number of observations, though 
we may never be able to say for certain how evolution has selected these 
functions.

I'll assume you know enough about the chemistry of RNA and DNA to bypass 
some of the normal introductory discussion.  The only chemical difference 
between RNA and DNA is the presence of 2'OH on the ribose of RNA.  This has 
pronounced effects on the structure and stability of RNA as compared to 
DNA.  The most obvious changes observed between ribose and deoxyribose 
sugars are in the distribution of sugar puckers; C3'-endo versus C2'-endo 
conformations dominate duplex RNA and DNA, respectively  (Note that single 
deoxy- or ribonucleotides generally have a C2'-endo conformation, though 
there is distribution of sugar conformations for isolated nucleotides).  In 
double-helical regions of nucleic acids, the sugar conformation affects the 
major and minor groove widths, the rise per base pair, the average axial 
diameter, and the twist angle.  In general, the 2'-OH is involved in 
hydrogen-bonding interactions with water, in duplex RNA regions, so this 
does not directly impact the structure or distribution of structures on its 
own.  In short, the presence or absence of the 2'-OH in RNA and DNA has 
immediate though indirect effects on the structure of nucleic acids.

In terms of thermodynamic stability, it is known that duplex RNA is more 
stable than duplex DNA.  The stability of double-stranded nucleic acids can 
be described a number of ways.  In addition to cross-strand hydrogen 
bonding interactions between bases, the stacking interactions between 
successive base pairs contributes significantly to the measured stability 
of short regions of either DNA or RNA.  It is known that stabilization from 
stacking interactions comes from nearest neighbor interactions, and does 
not propagate beyond the adjacent base pairs.  (In fact, you can use 
published thermodynamic values to predict the stability of a particular 
duplex RNA or DNA sequence with surprising accuracy).  The bottom line, 
using base pairing rules, is that short regions of RNA are more stable than 
short regions of DNA, by roughly 0.5 kcal/mol/base pair.

Another measure of nucleic acid stability is the persistence length, a bulk 
property of long double-stranded nucleic acids.  The persistence length is 
a measure of the rigidity of a polymer, simply the average distance over 
which a DNA or RNA molecule behaves like a rod.  If you think of a long 
polymer (1000 base pairs of DNA, or more), it will be rigid over short 
regions and can be approximated by a perfect double-helix; over the entire 
length of the chain, it will tend to bend.  The persistence length can be 
thought of as an arbitrary chain length over which the polymer behaves like 
a rigid rod.  For DNA, the persistence length is approximately 450-500 
angstroms; for RNA, the persistence length is on the order of 700-750 
angstroms, roughly 1.5 times as rigid as DNA.  So the bulk properties of 
DNA and RNA again indicate that RNA is more stable than DNA.

Now, consider the conformations of natural RNA and DNA molecules, in 
particular comparing ribosomal RNA versus genomic DNA.  As you know, 
genomic DNA exists in a double-helical conformation across its entire 
length.  (Note that single-stranded DNA viruses are an exception, only in 
the case of how the DNA is packaged; the functional form of viral DNA in 
infected cells is also in the duplex form).  On the other hand, structured 
RNA molecules are comprised of short double-stranded regions (between 4 and 
10 base pairs), interspersed by non-helical regions, either bulges, 
internal loops or hairpin loops.  (Note the exception of messenger RNA 
which is in generally single-stranded; in fact, most mRNA sequences can 
adopt various base-pairing schemes, but are held in the single-stranded 
conformation by RNA binding proteins, facilitating ribosomal translation). 
 In short, stretches of duplex DNA are long and contiguous; duplex regions 
of RNA are short and interrupted.

The structural differences between duplex RNA and DNA should give you a 
clue why this pattern is observed.  Proteins that interact with DNA and RNA 
must be able to bind uniquely to a particular sequence; thus proteins use 
the nucleotide bases for specificity.  The minor groove in either RNA or 
DNA is accessible to proteins, but the hydrogen bonding donors and 
acceptors presented by either G-C or A-T(U) bases are very similar, making 
sequence-specific recognition of the minor groove impossible.  For DNA 
binding proteins, sequence-specific protein interactions typically occur in 
the major groove of the duplex DNA.  However, the major groove of RNA is 
too deep and narrow to permit facile access to proteins.  It is generally 
observed that sequence-specific RNA:protein interactions occur in non-base 
paired regions; the internal loops, bulges, and hairpin loops, and perhaps 
the closing base pairs, are targets for sequence specific protein 
recognition.  This is particularly important for functional RNA molecules: 
 ribosomal RNAs, transfer RNAs, small nuclear RNAs, those molecules that 
have enzymatic activity that require proteins as co-factors.  These same 
RNAs also form complex tertiary structures; knotted looking structures 
where long-range RNA-RNA contacts are often observed.  The role of the 2'OH 
in either RNA:protein or RNA:RNA interactions is prominent, and well 
documented for many systems that have been studied in detail, indicating 
its primary role is as a handle for additional hydrogen-bonding 
interactions that would not be possible in the case of DNA.

To put it another way, the main function of DNA we observe is one of 
information storage.  The proteins that interact with DNA do so 
transiently, over the life-cycle of the molecule, and only interact with 
short regions through direct major groove contacts.  Though duplex RNA 
tends to be more stable, the structural features of DNA allow it to be 
efficiently packaged when it is not being replicated or translated.  (If 
DNA were more rigid than RNA, it would be more costly both energetically 
and spatially to use as the storage material).  RNA structure is more 
diverse and inconsistent; the higher stability of RNA allows for 
non-helical regions to exist without disrupting the entire molecule.  Also, 
it means that DNA-binding proteins and RNA-binding proteins have evolved 
entirely different mechanisms through which they interact with their 
preferred targets.  

The main argument I can make from you stems from the idea of the "RNA 
World", that is the argument that RNA, not DNA, was the first pre-biotic 
molecule.  Life had to start somewhere, right?  The simplest requirements 
for the first pre-biotic molecule are that they can catalyze reactions, 
store information, and be self-replicating.  It should be obvious to you 
that, evolutionarily, proteins come after RNA or DNA, and are therefore not 
a candidate; since each amino acid is coded by three nucleotide bases, and 
protein synthesis in the ribosome requires incoming amino acids to be 
linked to tRNAs; basically, proteins did not come before RNA.  (There are 
more arguments against proteins being the pre-biotic molecule, but that's 
not your question).  Both DNA and RNA are basically the same in their 
capacity to store information.  It wasn't until Tom Cech at the University 
of Colorado, Boulder discovered the first catalytic RNA molecule in 1981 
that we could begin to make an argument for RNA.  Since then, researchers 
have demonstrated a range of catalytic functions for RNA molecules 
including self-replication, peptidyl-transfer reactions (linking an amino 
acid to RNA), cleavage reactions (both forward and backwards), and DNA 
polymerization.  These enzymatic functions do not require any protein; they 
do however require the 2'OH for catalysis, as well as anchoring long range 
RNA:RNA interactions required for stabilizing the catalytic RNA.  These 
functions have not been demonstrated for DNA.  Again, the argument for RNA 
being the first pre-biotic molecule are much longer than I've presented, 
but you get the idea.  These arguments are in part based on the structural 
and functional differences between RNA and DNA outlined above.  Note too 
that deoxyribonucleotides are synthesized from ribonucleotides through a 
single reduction reaction; our cells spend a tremendous amount of energy 
making RNA precursors through very complex pathways, yet DNA precursors are 
generated from RNA precursors through a single reaction.  We can then argue 
that life began with RNA, and added in DNA as a functional molecule much 
later.

Lastly, ask yourself how evolution would have proceeded from there.  If RNA 
is the first functional molecule, why use DNA (or proteins) at all?  Why 
are we not just RNA beings?  Given that > 99% of our metabolic reactions 
are mediated by proteins, suggesting that the functional diversity of RNA 
as catalysts may be limited.  We can guess that proteins are simply more 
acrobatic in terms of the kinds of reactions they can catalyze, with new 
enzymes evolving out of protein as their functions were needed.  The 
evolution of DNA as a storage medium may have to do with a need to 
compartmentalize a cell.  Life requires that a cell be able to replicate 
itself, so the cell must contain all the necessary information for the 
cell's life cycle.  We can guess that it is more efficient to separate the 
functions we observe for DNA and RNA by separating them chemically.  Their 
structural and energetic differences may have meant that different classes 
of proteins would evolve to interact with either DNA or RNA; thus 
replication machinery would not interact with ribosomal machinery or vice 
versa.  The added bonus of DNA being more flexible than RNA might be 
responsible for the fact that DNA can be more readily packaged and 
protected from degradation when certain stages of a cell's life cycle are 
dormant.

In summary, DNA is not necessarily better suited to carry genetic 
information than RNA, it is more likely that RNA was better suited to be 
the prebiotic molecule and that RNA is better suited for other functions 
that DNA may not be able to perform.  The function of DNA as a receptacle 
for genetic information is likely to have evolved after the various 
functions of RNA were firmly in place.

For additional reading, check out the following textbooks, or refer to any 
introductory level biochemistry or molecular biology textbook:


     "Biochemistry" 4th ed., Lubert Stryer, New York: W.H. Freeman,
            QP514.2.S66 1995

     "Genes VII", Benjamin Lewin, New York: Oxford University Press,
            QH430.L487 1999

     "The RNA World: the nature of modern RNA suggests a prebiotic
            RNA", R. F. Gesteland, T. R. Cech, eds., New York: Cold
            Spring Harber Laboratory Press, QP623.R6 1999


I hope this helps (and in the future, please don't forget to supply your 
name so myself or other moderators can address your questions personally).

Regards,
Dr. James Kranz
University of Pennsylvania



Steve Mack adds:

The chemical difference between RNA and DNA (the absence of the 2'
hydroxyl group) makes DNA a good permanent information storage
molecule, while RNA is used for temporary information storage.
Because ribose has both 2' and 3' hydroxyl groups, the 2' hydroxyl
can "attack" the phosphodiester bond in the presence of hydroxyl
radicals, which results in the phosphate backbone being broken. This
reaction can occur spontaneously at neutral pH and is called
auto-catalytic clevage. Because DNA does not have a 2' hydroxyl
group, DNA molecules cannot undergo auto-catalytic clevage, and are
therefore much more stable than RNA. In other words, the presence of
the 2' hydroxyl gives RNA molecules have a significnatly shorter
half-life than DNA molecules, which makes RNA much less useful as a
long-term information storage molecule.