James Watson's "Central Dogma"

We've covered proteins: polymers of amino acid monomers that fold up and perform most of the tasks in the cell.

We've also covered DNA: a polymer of nucleotide monomers found in the nucleus that provides the codes needed to make proteins.

What we need now is to better understand the relationship between these two kinds of macromolecules.

Fortunately, the relationship between the two was clarified in 1958 by James Watson of Watson and Crick fame (discoverers of the structure of DNA in 1953). Watson called the relationship Central Dogma given its centrality to all of molecular biology. Here's more or less how he drew it out:

Central Dogma: James Watson's overview of molecular biology. DNA makes DNA ("DNA replication"). DNA makes RNAs ("transcription"). RNAs make proteins ("translation").

I've been saying that DNA codes for proteins. That is correct. What that leaves out, though, is that RNA molecules are intermediaries between the DNA code (which lives inside the nucleus) and the protein product (that's built outside the nucleus in the cytoplasm).

The Central Dogma diagram makes three main claims (from left to right):

(1) DNA can make a DNA copy of itself (the process is called replication). This happens in the nucleus when the cell is about to divide and needs another copy of its genome for the new daughter cells. This process will soon be the focus of this blog.

(2) DNA can make an RNA copy of itself (the process is called transcription). This also occurs in the nucleus. The RNA copy then makes its way out into the cytoplasm where it will be used to make a protein.

(3) RNA can make a protein (the process is called translation). As I mentioned, this generally occurs in the cytoplasm or in organelles like the ER and Golgi apparatus.

There's a lot to clarify here. Let's start with the new macromolecule I just introduced: RNA.

What is RNA?

RNA is very similar to DNA. It's a macromolecule made of nucleotides that are just slightly different than the nucleotides used to make DNA. Also, in RNA, a nucleotide called uracil (U) replaces thymine (T). So in RNA, U pairs with A.

RNA molecules serve different purposes in the cell. I'm not going to describe them all. The kind that's important here is called mRNA, where the 'M' stands for "messenger."

Think of mRNA as the cell's version of a photocopy of DNA operating instructions. Given that a cell has only one copy of its two genomes, it can't take a risk that it'll be damaged. So DNA is kept safe in the nucleus. When its time to make a bunch of a given protein, the cell makes multiple mRNA copies of the gene. It's the code in these mRNAs that's used to make the proteins.

Replication (DNA > DNA)

We'll be spending about half of this blog discussing DNA replication so here I'll just mention that many, many proteins are involved in the process, but the primary one is an enzyme called DNA polymerase. It is called a "polymerase" because it synthesizes a polymer (DNA). The names of enzymes usually end with the suffix "-ase."

A quick aside. Although this blog focuses on the details of DNA replication, I could have easily made it about the details of transcription or of translation. They are equally sophisticated processes. Here, though, I just want to provide an overview of each so you'll have cellular context.

Transcription (DNA > RNA)

To ultimately make a protein, the cell first performs transcription: in the nucleus it makes many mRNA copies of a gene coded in the DNA. Then it sends those mRNA copies out into the cytoplasm where they participate in translation (our next topic).

Transcription: DNA polymerase (light blue) opens the double helix to make the template strand (dark gray) accessible. It then successively adds RNA nucleotides complementary to the DNA template to build the final mRNA (red). A Poly A tail will be added after the mRNA is released by the RNA polymerase (not shown).

The trick to making RNAs (including mRNAs) is complementary base pairing. An example. Let's say we have a gene that starts with the start codon (ATG) and then includes just two other codons before reaching the stop codon. The two codons before the stop codon are for arginine (codon = AGA) and serine (codon = TCA). We'll use the stop codon TAA. The stop codon doesn't add an amino acid. So the polypeptide created by this gene will only have three amino acids: Met-Arg-Ser.

Below I show the complete gene and its complement (the template strand). I added spaces to emphasize codons. Also note the "5'" and "3'" that indicate the direction in which the gene must be read.

Our gene: 5' ATG AGA TCA TAA 3'

The gene's complement (template strand): 3' TAC TCT AGT ATT 5'

This gene will be located on one of the two DNA strands in a double helix. If we want a copy of this gene in RNA, we simply access the DNA on the strand opposite the gene of interest (that is, the nucleotide stretch complementary to our gene). If we add complementary RNA nucleotides to that strand (now referred to as the template strand) that are complementary to our gene, we'll end up with an mRNA copy of our gene!

As I mentioned earlier, in all RNAs the nucleotide uracil (U) is used instead of thymine (T). So the mRNA "photocopy" of our three amino acid gene would look like this:

mRNA copy of our gene: 5' AUG AGA UCA UAA 3'

But how does this happen? In the nucleus, a protein called RNA polymerase adds RNA nucleotides to the gene's complementary sequence (the template strand). RNA polymerase begins by sitting down on the DNA sequence that's complementary to the start codon, which would be the opposite of ATG, or TAC. The first nucleotide is a T. So RNA polymerase waits for its complement--an A RNA nucleotide--to arrive. When it does, RNA polymerase attaches it via weak hydrogen bond to the T. We now have a small one nucleotide mRNA.

Where did the A RNA nucleotide come from? Remember, metabolites like nucleotides are in constant rapid motion, frequently crashing into other molecules like RNA polymerase.

Next, the RNA polymerase slides one nucleotide down the template strand. The next DNA nucleotide is an A (the complement of the T in the start codon ATG). When a U happens to arrive, the RNA polymerase does two things. First, it attaches the U via weak hydrogen bond to the A in the template strand. Then it attaches this U to the first A of the now growing mRNA with a strong bond.

The RNA polymerase continues like this, sliding down the template strand adding complementary RNA nucleotides to the growing chain. Once RNA polymerase reaches the stop codon, the cell does something a little odd. It attaches 100-250 A nucleotides to the end of the mRNA (called the poly A tail). The poly A tail serves a few purposes including stabilizing the mRNAs from degradation and helping with their export out of the nucleus and into the cytoplasm. Once the mRNA is in the cytoplasm, the poly A tail shrinks little by little as the mRNA is used for translation (i.e., for making proteins). When the polyA tail gets too short, the cell degrades the mRNA.

Translation (RNA > Protein)

We now have an mRNA that's an exact copy of our gene that has made its way out of the nucleus and into the cytoplasm. We'll need the code from the mRNA (that is, the codons) to know the order in which to add amino acids to the growing chain that will end up being our polypeptide and eventually our protein.

There are four actors in translation. First, there's our mRNA with its codons describing some future protein.

Second, we have molecular machines called ribosomes floating around the cytoplasm. Ribosomes are the molecular machines that create proteins from an mRNA and raw materials (amino acids). I have said frequently that proteins do (almost) all the work in the cell. Ribosomes are one of the exceptions. A ribosome is definitely a molecular machine. But it's made of both proteins and RNAs (specifically, ribosomal RNAs, or rRNAs).

Third, there are all 20 amino acids floating around the cell as well. Fourth, and finally, there are transfer RNAs (tRNAs). As we'll see, tRNAs are the key to translation because they speak two languages: the language of DNA and the language of proteins.

tRNA are highly specific. A portion of every tRNA consists of a three-letter anticodon (that is, the complementary three nucleotides to some specific codon). Another portion of every tRNA attaches to one, and only one, amino acid. And with every tRNA, its anticodon is the correct anticodon given the specific amino acid to which it attaches.

Theoretically, there should be 61 tRNAs (64 codons minus three stop codons). But it so happens that the last of the three nucleotides in a codon are less important that the first two. So the cell is able to get by with about 48 different tRNAs.

In translation, a tRNA floating around the cytoplasm attaches to its correct amino acid (based on shape, of course). At the same time, a ribosome attaches to an mRNA. The ribosome is large enough that it covers about three codons. When the tRNA corresponding to the first codon crashes into the ribosome (By "corresponding" I mean that the tRNAs anticodon matches the mRNAs first codon.)

The tRNA anticodon now physically binds its anticodon to its complementary sequence--the first codon in the mRNA. This positions the first amino acid within the ribosome.

Now the next tRNA (that is, the tRNA with an anticodon that is the complement of the second codon on the mRNA) arrives at the ribosome. It, too, attaches physically to the mRNA codon using its anticodon. Now we have two amino acids lined up next to each other based on their being attached to the first two correct tRNAs. Now its just a matter of the ribosome creating a strong peptide bond between the first and second amino acids. This process continues until the complete polypeptide has been synthesized.