13.1 DNA structure and topology

DNA Structure and Key Components

DNA stores all the genetic information a cell needs to function and reproduce. Understanding its physical structure explains how it gets copied so accurately and why certain structural features matter for processes like transcription and repair.

Structure of the DNA Double Helix

Two polynucleotide strands wind around each other in a right-handed double helix, running in opposite directions (antiparallel). Each strand has three chemical components:

• Deoxyribose, a five-carbon (pentose) sugar
• Phosphate groups that link the 3' carbon of one sugar to the 5' carbon of the next, forming the sugar-phosphate backbone
• Nitrogenous bases attached to each sugar: adenine (A), thymine (T), guanine (G), and cytosine (C)

The two strands are held together by hydrogen bonds between complementary base pairs:

• A pairs with T through two hydrogen bonds
• G pairs with C through three hydrogen bonds (making G-C pairs slightly more stable)

The double helix also has a major groove and a minor groove. These aren't just geometric features. Proteins like transcription factors read the sequence of bases by docking into the major groove, where more of each base pair is chemically exposed.

Antiparallel Structure and Base Pairing

The two strands run in opposite directions: one reads 5'→3' while the other reads 3'→5'. This antiparallel arrangement is what allows a stable helix to form, because the base pairs stack evenly along the interior of the molecule.

It also has direct functional consequences:

• Semiconservative replication: each strand serves as a template for a new complementary strand, so both daughter molecules contain one old and one new strand.
• Accuracy: complementary base pairing enforces specificity during replication and transcription. A polymerase "knows" which nucleotide to add because only the correct complement fits geometrically and forms the right hydrogen bonds.
• Repair: if one strand is damaged, the intact complementary strand provides the information needed to restore the correct sequence.

DNA Conformations and Topology

Conformations of DNA

DNA doesn't always look the same. The double helix can adopt different shapes depending on the local environment and sequence context.

• B-DNA is the most common form under normal physiological conditions. It's a right-handed helix with about 10.5 base pairs per turn, a wide major groove, and a narrow minor groove. This is the "textbook" conformation.
• A-DNA forms under dehydrating conditions (e.g., in the presence of ethanol). It's also right-handed but more compact, with 11 base pairs per turn. Its major groove is deep and narrow, while its minor groove is wide and shallow. RNA-DNA hybrids and double-stranded RNA tend to adopt A-form geometry.
• Z-DNA is the odd one out: a left-handed helix with 12 base pairs per turn. It's narrower and more elongated than B-DNA. Z-DNA tends to form in regions with alternating purine-pyrimidine sequences, particularly stretches of alternating G and C. There is evidence that Z-DNA plays a role in gene regulation, though its biological functions are still being studied.

DNA Supercoiling and Topoisomerases

Inside cells, DNA doesn't just sit as a relaxed helix. It gets twisted further, coiling around its own axis in a process called supercoiling.

• Positive supercoiling means the DNA is overwound (tighter than relaxed B-DNA).
• Negative supercoiling means the DNA is underwound, which makes it easier to separate the strands for replication and transcription. Most genomes are negatively supercoiled.

Supercoiling is described mathematically by the linking number equation:

$Lk = Tw + Wr$

• Twist ($Tw$): the number of times the two strands wind around each other (helical turns).
• Writhe ($Wr$): the number of times the helix axis crosses over itself (think of a coiled phone cord twisting on itself).

The linking number $Lk$ is a topological property, meaning it can only change if you break one or both strands. That's where topoisomerases come in.

How topoisomerases work:

1. Type I topoisomerases cut one strand of the double helix, allow the DNA to rotate and relieve torsional stress, then reseal the break. They change $Lk$ by increments of 1.
2. Type II topoisomerases cut both strands, pass another segment of the double helix through the gap, then reseal the break. They change $Lk$ by increments of 2.

Both types are essential for replication and transcription, where unwinding the helix ahead of the polymerase would otherwise create unsustainable positive supercoils.

Because topoisomerase inhibition traps broken DNA and triggers cell death, these enzymes are major drug targets. Etoposide (a chemotherapy drug) poisons human topoisomerase II, while ciprofloxacin (an antibiotic) targets bacterial DNA gyrase, a type II topoisomerase found only in prokaryotes.