What Is the Difference Between Continuous & Discontinuous DNA Synthesis?

The structure of DNA is like a rope ladder, but with two anti-parallel strands that run in opposite directions. During replication, protein machines split the two strands apart to allow proteins called polymerases to copy the two strands into four strands, which combine to form two separate ladders. DNA Polymerase delta (Pol delta), the main polymerase in DNA replication, can only travel in one direction of the ladder, while having to copy both anti-parallel strands. Its dilemma is that it can only read and copy strands in the tail-to-head (called 3’ to 5’) direction. Thus, it reads one strand tail-to-head (let’s call this strand 1) in a straightforward way, but must grab the other strand (let’s call this strand 2), which from Pol delta’s perspective is head-to-tail (5’ to 3’), and loop it into a spiral. The point of the circular spiral is that one region of the spiral is now in the same tail-to-head direction as strand 1. Pol delta can now read and copy this short region of strand 2 while copying strand 1. These extra maneuvers for strand 2 cause it to be copied in short pieces, and is thus called discontinuous DNA synthesis. The straightforward copying of strand 1 happens uninterrupted, and is called continuous DNA synthesis. Specialized proteins perform each type of synthesis.

Continuous DNA synthesis occurs when DNA Polymerase delta reads and copies one strand of the DNA template in an uninterrupted fashion. Pol delta travels along this strand in the 3’ to 5’ direction (tail-to-head), matching each base pair on the template with a corresponding nucleotide. Pol delta is a high fidelity polymerase, meaning it can make long copies of a template without stopping. Pol delta is part of a large complex of proteins, which includes an arm that reaches in front of the unzipping DNA ladder and grasps (encircling it, like a doughnut) the still-zipped region. In this way, it can better hang on to the DNA ladder as it moves along making copies. Pol delta has high fidelity; meaning can make new strands that are 30,000 nucleotides long before falling off.

Discontinuous DNA synthesis is the copying of a DNA template strand in short fragments and then combining them into one long strand. Because Pol delta has to turn the head-to-tail (5’ to 3’) strand into a loop, which still slides through the grips of Pol delta as it moves in one direction down the ladder, it can only copy parts of this strand that are momentarily tail-to-head. These short fragments are called Okazaki fragments, and in one mammalian cell cycle, 50 million fragments are made. DNA Pol delta is responsible for making these fragments, which are only around 200 nucleotides long.

Another major difference between continuous and discontinuous synthesis is the number of primers for each. A primer is a short stretch of RNA that is bound to the unzipped DNA strands. This stretch of RNA is the starting line for DNA Polymerase delta to climb on and start copying. Primers are attached to unzipped DNA by enzymes called primases. Since continuous DNA synthesis makes only one strand, it needs only one primer to start it off. Discontinuous DNA synthesis, however, produces 50 million Okazaki fragments. Since each Okazaki fragment needs a primer to start it off, discontinuous synthesis would need just as many primers as there are Okazaki fragments.

Discontinuous DNA synthesis results in many Okazaki fragments that need to be merged. Thus, this type of synthesis requires more enzymes than continuous synthesis. An enzyme called primase lays down a primer that is 7-14 RNA nucleotides long. Then, DNA Pol alpha, which partners with primase, extends the RNA primer with another 20 nucleotides, but using DNA nucleotides. Next, DNA Pol delta, the main polymerase, extends the 20 DNA nucleotides with another 200 DNA nucleotides to produce one Okazaki fragment. In order to merge the fragments, enzymes called Fen1, Rnase H, and Dna2 replace the RNA primers at the start of each Okazaki fragment, and then ligate, or fuse, the fragments into one long strand.