A topic in the Open Knowledge Graph — a free, open map of 15,290 topics and the order to learn them in.
DNA replication copies the genome before cell division using a semi-conservative mechanism: each daughter molecule retains one original strand and one newly synthesized strand. DNA polymerase reads the template 3' to 5' and synthesizes the new strand 5' to 3', requiring a short RNA primer to initiate. The leading strand is synthesized continuously, while the lagging strand is built in discontinuous Okazaki fragments that are later joined by DNA ligase. Multiple origins of replication on eukaryotic chromosomes allow the large genome to be replicated efficiently.
Draw the replication fork showing helicase unwinding, primase adding primers, and both polymerases extending. Work through why one strand is continuous and the other discontinuous given the 5'-to-3' constraint.
Every cell division requires an exact copy of the genome to be passed to each daughter cell. DNA replication accomplishes this with remarkable fidelity — but understanding how it works requires thinking carefully about the constraints imposed by DNA chemistry and the enzymes that copy it.
The central feature of replication is that it is *semi-conservative*: each of the two strands of the original double helix serves as a template for synthesizing a new complementary strand. When replication is complete, you have two identical double-stranded molecules, each consisting of one original parental strand and one newly synthesized strand. This was confirmed by the Meselson-Stahl experiment: bacteria grown in heavy-nitrogen (¹⁵N) medium were shifted to normal (¹⁴N) medium, and after one generation the DNA had exactly intermediate density — one ¹⁵N strand and one ¹⁴N strand per molecule — consistent with semi-conservative replication and ruling out both conservative and dispersive models.
The molecular machinery begins at specific DNA sequences called *origins of replication*. Helicase unwinds and separates the two strands, creating a replication fork. Single-strand binding proteins stabilize the exposed strands and prevent them from reannealing. Then comes a critical chemical constraint: DNA polymerase can only add nucleotides to the 3'-OH end of an existing strand — it cannot initiate a new strand from scratch. This is why *primase* (an RNA polymerase) first synthesizes a short RNA primer, providing the 3'-OH group that DNA polymerase needs to begin extension. After replication, these RNA primers are removed and replaced with DNA, and any gaps are sealed by DNA ligase.
The antiparallel nature of the two template strands creates a fundamental asymmetry at the replication fork. DNA polymerase always synthesizes in the 5'→3' direction, reading the template 3'→5'. On the *leading strand*, the template runs 3'→5' in the direction of fork movement, so DNA polymerase can extend continuously toward the fork. On the *lagging strand*, however, the template runs 5'→3' toward the fork — meaning polymerase must work *away* from the fork. As helicase unwinds more template, primase must repeatedly lay down new RNA primers, and polymerase synthesizes short segments called *Okazaki fragments* in the opposite direction to fork movement. These fragments are later joined by DNA ligase into a continuous strand.
Eukaryotic chromosomes are vastly larger than prokaryotic chromosomes, so replicating from a single origin would take weeks. Eukaryotes solve this by firing many *origins of replication* simultaneously — hundreds to thousands per chromosome. Replication proceeds bidirectionally from each origin, creating expanding bubbles that merge as replication converges from neighboring origins. Strict regulation ensures each origin fires exactly once per cell cycle, preventing over-replication. This mechanism allows the entire human genome (about 6 billion base pairs) to be accurately copied within hours during S phase of the cell cycle.