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Before a cell can divide, it must make an accurate copy of every chromosome — every base of its DNA. The process by which this is achieved is called DNA replication. This lesson covers the OCR A-Level Biology A specification point 2.1.3 (e) — the semi-conservative nature of DNA replication, the roles of DNA helicase and DNA polymerase, and the classic Meselson–Stahl experiment that proved semi-conservative replication was correct.
When the structure of DNA was first solved, three competing hypotheses existed for how it is replicated:
graph TD
A[Parental DNA] --> B[Conservative: one all-old, one all-new]
A --> C[Semi-conservative: each daughter = 1 old + 1 new strand]
A --> D[Dispersive: patches of old and new on both strands]
Only the semi-conservative model turned out to be correct — as demonstrated by Meselson and Stahl in 1958.
Matthew Meselson and Franklin Stahl devised a beautifully elegant experiment using isotopes of nitrogen:
| Sample | Observed band(s) | Interpretation |
|---|---|---|
| Before transfer (all ¹⁵N) | A single heavy band | All DNA contains only ¹⁵N |
| After 1 generation | A single intermediate band | Each molecule contains one ¹⁵N strand and one ¹⁴N strand — refutes conservative model |
| After 2 generations | Two bands — one intermediate, one light | Half the molecules are hybrid, half are entirely light — refutes dispersive model |
The results matched the predictions of the semi-conservative model exactly, and ruled out both the conservative and dispersive hypotheses.
Exam Tip: You should be able to predict the banding patterns expected under each model and explain why the observed results support semi-conservative replication.
The modern understanding of replication includes several named enzymes and a clear sequence of events.
graph TD
A[Double helix] --> B[DNA helicase breaks H-bonds]
B --> C[Strands separate at replication fork]
C --> D["Free nucleotides pair with exposed bases<br/>A–T, C–G"]
D --> E["DNA polymerase joins nucleotides<br/>by phosphodiester bonds"]
E --> F["Two identical daughter double helices<br/>each: 1 old strand + 1 new strand"]
Free DNA nucleotides arrive at the replication fork not as monophosphates (one phosphate) but as nucleoside triphosphates (three phosphates, like ATP but with different bases). When DNA polymerase incorporates a nucleotide into the growing strand, it cleaves off two phosphate groups (as pyrophosphate, PPi), releasing energy that is used to form the phosphodiester bond.
You do not need to go further than knowing that nucleotide polymerisation requires energy and that activated (triphosphate) nucleotides provide it.
| Enzyme | Role |
|---|---|
| DNA helicase | Breaks the hydrogen bonds between complementary bases, unwinding and separating the two strands of DNA. |
| DNA polymerase | Catalyses the formation of phosphodiester bonds between adjacent nucleotides, joining them into a new polynucleotide strand that is complementary to the template. It also performs "proofreading" to correct errors. |
OCR does not require you to name other enzymes involved in replication (primase, ligase, topoisomerase) but if you are aiming for A/A*, it helps to be aware that the real process is more elaborate.
Replication is extremely accurate. The base-pairing rules mean that each new nucleotide is almost always added correctly; in addition, DNA polymerase has a proofreading function — it can detect mismatched bases and remove them before extending the strand.
The error rate after proofreading is approximately 1 in 10⁹ base pairs — roughly one mistake per genome per cell division in humans. Errors that do escape correction (and are not fixed by other repair enzymes) become mutations — the raw material of evolution, but also the cause of most cancers.
Exam Tip: Questions may ask why replication must be so accurate. Good answers include: so that daughter cells inherit the correct genes; so that proteins are still made correctly; to prevent mutations that could lead to disease such as cancer.
Model answer for (3): "DNA helicase breaks the hydrogen bonds between complementary base pairs, unwinding the double helix so the two strands can separate. DNA polymerase catalyses the formation of phosphodiester bonds between adjacent nucleotides to build new strands complementary to each template."
Spec Mapping: This lesson is mapped to OCR H420 Module 2.1.3 — Nucleotides and nucleic acids, covering the semi-conservative replication of DNA, the roles of named enzymes (helicase, DNA polymerase, ligase) and the experimental evidence of the Meselson–Stahl experiment (refer to the official OCR H420 specification document for exact wording).
DNA replication is the most heavily examined topic in Module 2.1.3. The combination of mechanism + experimental evidence (Meselson–Stahl) is a recurring 9-mark / extended-response anchor. Candidates also need to discuss the consequences of replication errors for mutation and to explain why semi-conservative replication, not conservative or dispersive, is consistent with the experimental data.
When Watson and Crick proposed the double helix in 1953, three replication models were biologically plausible:
| Model | Mechanism | Prediction after one round of replication in ¹⁴N |
|---|---|---|
| Conservative | The parental helix remains intact; a new helix is synthesised entirely from new nucleotides | Two bands: original ¹⁵N (heavy) + new ¹⁴N (light) |
| Semi-conservative | The two parental strands separate; each acts as a template; new helices are half-old, half-new | One band at intermediate density (¹⁵N/¹⁴N hybrid) |
| Dispersive | The parental helix is fragmented; new DNA is interspersed with old | One band at intermediate density (¹⁵N/¹⁴N hybrid) |
After two rounds, the predictions diverge sharply:
| Model | Prediction after two rounds in ¹⁴N |
|---|---|
| Conservative | Two bands: heavy (original) + light |
| Semi-conservative | Two bands: intermediate + light |
| Dispersive | One band, progressively lighter |
Matthew Meselson and Franklin Stahl (1958), using density-gradient ultracentrifugation in caesium chloride, observed exactly the two-band semi-conservative pattern after two rounds — ruling out both conservative and dispersive models in a single elegant experiment. The Meselson–Stahl experiment is often described as "the most beautiful experiment in biology" because the predictions of the three models diverged so cleanly that the result was unambiguous.
graph TD
A["Parental DNA grown in ¹⁵N<br/>(heavy)"] --> B["Transfer to ¹⁴N medium"]
B --> C["Round 1: hybrid band only<br/>rules OUT conservative"]
C --> D["Round 2: hybrid + light bands<br/>rules OUT dispersive"]
D --> E["Semi-conservative confirmed"]
The basic Watson–Crick proposal needed elaboration once Arthur Kornberg (1956) isolated DNA polymerase I from E. coli, showing that nucleotide polymerisation required a template, a primer, and the dNTP precursors. Kornberg won the 1959 Nobel Prize for this work. Subsequent work identified the additional players: DNA helicase (unwinding), primase (RNA primer synthesis), DNA polymerase III (the principal bacterial replicative polymerase), DNA ligase (joining Okazaki fragments), and single-stranded binding proteins (preventing reannealing). The school of thought to take into the exam is "replication is a team enzymology — no single enzyme can do it alone".
This lesson connects forward to:
ocr-alevel-biology-nucleic-acids-enzymes — Enzyme action (Lesson 9): every enzyme in the replication machinery is itself a protein whose active-site geometry obeys the lock-and-key / induced-fit principles you meet later in this course.ocr-alevel-biology-genetics-inheritance — Mutations: errors during replication are the principal source of point mutations. DNA polymerase has 3'→5' exonuclease proofreading activity, but is not infallible.ocr-alevel-biology-cell-structure — Cell cycle: DNA replication occurs in S-phase of interphase, preparing the cell for mitosis or meiosis.ocr-alevel-biology-genetics-inheritance — DNA fingerprinting and PCR: the polymerase chain reaction uses a thermostable DNA polymerase (Taq) to replicate DNA in vitro — a direct application of the chemistry of this lesson.ocr-alevel-biology-photosynthesis-respiration — ATP: dNTPs are nucleoside triphosphates whose hydrolysis provides the chemical energy that drives the formation of the phosphodiester bond, just as ATP hydrolysis drives the muscle and active-transport reactions you meet in Module 5.Question (9 marks): Describe and explain the process of semi-conservative DNA replication. Evaluate the experimental evidence that supports the semi-conservative model rather than the conservative or dispersive alternatives.
Mark scheme decomposition (AO breakdown):
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