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Chapter 11 · Part 8 of 10
  1. Chapter overview
  2. 1Identifying the genetic material
  3. 2Nucleotides: the building blocks
  4. 3Strands and the double helix
  5. 4Discovering the double helix
  6. 5Semiconservative replication
  7. 6Opening the fork and building DNA
  8. 7Leading and lagging strands
  9. 8Accuracy and the ends of chromosomes
  10. 9Packing DNA into nucleosomes and loops
  11. 10Organizing and condensing chromosomes

Accuracy and the ends of chromosomes

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Copying billions of nucleotides at high speed invites mistakes, yet DNA replication almost never leaves one behind. Another challenge waits at the very tips of linear chromosomes, where the usual copying machinery can’t finish the job.

Replication is very accurate

A process that makes very few mistakes has high fidelity. In bacteria, DNA replication leaves only about 1 permanent mistake per 100 million nucleotides. Three features account for this:

  1. Correct pairs are more stable. Hydrogen bonds between A and T, or G and C, hold together better than those in a mismatched pair.
  2. The polymerase checks the fit. DNA polymerase’s active site (the pocket where it does its chemistry) is unlikely to bond a new nucleotide into the strand if it is mismatched with the template.
  3. The polymerase fixes its errors. If a wrong nucleotide does get added, DNA polymerase detects the mismatch, backs up, and removes nucleotides from the end of the new strand, working in the 3′ to 5′ direction. Once the mistake is gone, it switches back and resumes building 5′ to 3′. This error correction is proofreading.

A family of DNA polymerases

Replication has to be fast, accurate, and complete, with no gaps left behind. No single enzyme does all of that equally well, so cells make several DNA polymerases, each specialized. E. coli has 5, and humans have 12 or more.

These enzymes arose through evolution. Copies of a polymerase gene were duplicated by chance, mutations changed each copy, and natural selection kept versions whose properties suited the organism.

Organism Polymerase Main job
E. coli III Copies most of the DNA
E. coli I Removes RNA primers and fills in the gaps
E. coli II, IV, V Repair damaged DNA and copy past damage
Human α (alpha) Has a built-in primase; makes RNA primers and short DNA stretches
Human δ (delta), ε (epsilon) Take over from α and copy rapidly; δ makes the lagging strand, ε the leading strand
Human γ (gamma) Copies mitochondrial DNA
Human Translesion polymerases Copy past damaged spots that stall the main polymerases

The main polymerases stall when they hit a damaged spot in the template, called a lesion. Specialized polymerases can copy across it. They are slower, but they make sure replication is completed.

The problem at chromosome ends

Bacterial chromosomes are circles, so they have no ends. Eukaryotic chromosomes are linear, and their tips pose a copying problem.

The tip of each eukaryotic chromosome is a telomere: a short DNA sequence repeated anywhere from a few dozen to several hundred times. In humans the repeat is 5′–GGGTTA–3′. At the very end, one strand sticks out past the other, forming a single-stranded 3′ overhang.

DNA polymerase needs a primer and builds only 5′ to 3′. At the extreme end of a template strand’s 3′ end there is no room to lay down a primer and fill in from it, so that tip can’t be copied. Without a fix, a linear chromosome would get a little shorter every time it was replicated.

Telomerase extends the ends

The fix is an enzyme called telomerase, which adds extra copies of the telomere repeat to chromosome ends. Telomerase is made of both protein and RNA, and its RNA contains a sequence complementary to the telomere repeat.

  1. Part of telomerase’s RNA pairs with the repeat sequence in the 3′ overhang, binding the enzyme to the chromosome end.
  2. Using the rest of its RNA as a template, telomerase adds six DNA nucleotides, one new repeat, to the 3′ end.
  3. Telomerase shifts to the new end and adds another repeat, over and over, greatly lengthening the 3′ end.
  4. The lengthened end now leaves room for primase to make an RNA primer. DNA polymerase fills in the complementary strand, and DNA ligase seals it.
5′ 3′ 5′ 3′ Telomere repeats New repeats 3′ overhang Telomerase RNA template Shift andrepeat
Figure 11.6 Telomerase carries its own RNA template. It pairs with the end of the overhang, adds one repeat, then slides along to add the next.

Telomerase and cancer

Cancer cells divide over and over without stopping. In about 90% of human cancers, telomerase is present at high levels. By keeping telomeres from shortening, it may help cancer cells continue to divide. How cancer cells boost telomerase activity is still being studied.

Check yourselfWhy doesn’t a bacterial chromosome need telomerase, while a human chromosome does?

A bacterial chromosome is circular, so it has no ends where copying can fall short. A human chromosome is linear, and because DNA polymerase needs a primer and builds only 5′ to 3′, it can’t copy the very tip of each end. Telomerase lengthens the ends so the chromosome doesn’t shrink.

Practice questions

  1. 1 of 2

    While building a new strand, DNA polymerase adds a G across from a T in the template. What happens during proofreading?

  2. 2 of 2

    Which feature helps make DNA replication so accurate?