When a cell copies its chromosomes, it unzips each DNA double helix and builds two identical versions of every chromosome during a phase called S phase (synthesis phase). The entire process takes several hours in human cells and involves dozens of specialized proteins working together to duplicate roughly 6.4 billion base pairs of DNA with extraordinary accuracy. By the end, the cell holds twice its normal amount of genetic material, with each chromosome existing as a pair of identical copies held together until the cell divides.
When and Why Copying Begins
Chromosome copying doesn’t happen continuously. It’s confined to S phase, one stage of the larger cell cycle that a cell moves through before dividing. Before S phase begins, the cell spends time in a growth period called G1, where it increases in size and prepares the molecular machinery it will need. The transition into S phase is controlled by rising levels of a protein called CDK2, which acts like a switch. As CDK2 activity climbs, it shuts down a molecular brake (a complex called APC/C) that had been preventing replication from starting. Once that brake is released, DNA synthesis begins.
The timing matters because copying chromosomes at the wrong moment, or copying them twice, would be catastrophic. The cell uses multiple overlapping safeguards to ensure each stretch of DNA is replicated exactly once per cycle.
How the DNA Double Helix Gets Unzipped
DNA is a twisted ladder of two complementary strands. To copy it, the cell first has to pull those strands apart. Enzymes called helicases do this work, traveling along the DNA and prying open the double helix at speeds up to 1,000 base pairs per second. This creates a Y-shaped structure called a replication fork, where the two separated strands serve as templates for building new copies.
Replication doesn’t start at just one spot. Human chromosomes are so large that starting from a single point would take far too long. Instead, thousands of starting points (called origins of replication) fire across all 46 chromosomes during S phase, with replication forks spreading outward from each one. These individual stretches of copying eventually merge together to complete each chromosome.
Building the New Strands
Once the helix is open, the cell’s copying enzyme, DNA polymerase, reads each exposed strand and assembles a matching partner using free-floating building blocks called nucleotides. Each nucleotide carries a small energy packet (in the form of phosphate groups) that powers its own attachment to the growing chain. DNA polymerase links these nucleotides together one by one, always working in a single direction along the strand: from the 5′ end toward the 3′ end.
This one-way rule creates an asymmetry at every replication fork. One strand, called the leading strand, points in the same direction the fork is opening, so DNA polymerase can copy it in one smooth, continuous run. The other strand, the lagging strand, points the opposite way. The cell can’t copy it continuously, so instead it builds it in short segments roughly 100 to 150 nucleotides long, known as Okazaki fragments.
Each Okazaki fragment needs its own small starter piece. An enzyme called primase lays down a short RNA primer to give DNA polymerase a place to begin. After the polymerase extends the fragment, it bumps into the primer from the previous fragment. That RNA primer is then removed and replaced with DNA, and a final enzyme called ligase seals the gap by joining the fragments together into one continuous strand. Think of it like paving a road in sections and then welding the seams shut.
The Problem at Chromosome Tips
Linear chromosomes have a built-in vulnerability at their ends, called telomeres. On the lagging strand, when the very last RNA primer is removed, there’s no way for DNA polymerase to fill in the resulting gap because there’s nothing upstream to extend from. This means a small amount of DNA is lost from the chromosome tip every time a cell divides. On the leading strand, replication to the very end produces a blunt molecule that must be trimmed to create a normal chromosome tip structure, also resulting in sequence loss.
This is known as the end replication problem, first described in the early 1970s. To compensate, chromosome tips are capped with thousands of repeats of a simple DNA sequence that don’t encode any genes. These repetitive telomere sequences act as a disposable buffer. In cells that need to divide many times (like stem cells and immune cells), an enzyme called telomerase adds new repeats to the ends, counteracting the gradual shortening. Most ordinary body cells lack significant telomerase activity, which is one reason telomeres shorten with age.
How the Cell Catches Mistakes
DNA polymerase is remarkably accurate, but it’s not perfect. On its own, it misinserts the wrong nucleotide about once every 10,000 to 100,000 bases. For a human genome of 6.4 billion base pairs, that would mean tens of thousands of errors per round of copying if left uncorrected.
The first layer of quality control is built into the polymerase itself. It has a proofreading function: after adding each nucleotide, it checks whether the fit is correct. If the new base doesn’t pair properly with the template, the polymerase reverses, removes the mistake, and tries again. This proofreading step catches the vast majority of errors. When proofreading is experimentally disabled in lab mice, mutation rates jump more than 70-fold.
A second layer, called mismatch repair, scans the newly copied DNA after the polymerase has moved on. Specialized proteins detect mismatched bases, cut out the incorrect section, and fill it back in correctly. Together, proofreading and mismatch repair bring the final error rate down to approximately one mistake per 10 billion base pairs copied. That means a typical human cell division introduces roughly one new mutation across the entire genome.
What the Copied Chromosomes Look Like
After a chromosome is copied, the two identical DNA molecules don’t simply float apart. A ring-shaped protein complex called cohesin wraps around both copies and holds them together like a molecular handcuff. These paired copies are called sister chromatids, and they remain physically linked from the moment they’re made in S phase until the cell is ready to divide.
This pairing is essential. When the cell eventually enters mitosis, the machinery that pulls chromosomes apart can identify each pair of sister chromatids and send one copy to each daughter cell. Without cohesin holding them together, the cell would have no reliable way to tell which chromosomes are partners, and the division would go wrong.
The Final Check Before Division
Between the end of DNA copying and the start of cell division, there’s a gap called G2 phase. During this window, the cell runs a final quality check known as the G2/M checkpoint. This checkpoint surveys the genome for any remaining DNA damage or incomplete replication. If problems are detected, the cell halts the cycle by blocking the key protein (Cdc2) that would normally drive it into mitosis.
In cells with damaged DNA, the tumor suppressor protein p53 plays a central role. It works with other regulatory proteins to shut down production of the molecules needed for division, keeping the cell parked in G2 until repairs are finished. If the damage is too severe to fix, p53 can push the cell toward permanent arrest or programmed death, preventing a potentially dangerous cell from multiplying. This checkpoint is one of the most important cancer-prevention mechanisms in the body, and mutations that disable it are found in a large proportion of human tumors.