Chapter 13: Molecular Basis of Inheritance

Overview: Life’s Operating Instructions

The discovery of DNA's structure revolutionized our understanding of heredity. DNA contains the instructions for the development and functioning of all living organisms, and its accurate replication is essential for life.

• Double-Helical Model: Introduced by James Watson and Francis Crick in 1953, based on data from multiple researchers.

• Hereditary Information: DNA directs biochemical, anatomical, physiological, and some behavioral traits.

• DNA Replication: Ensures all cells inherit identical genetic information.

13.1 DNA is the Genetic Material

Evidence for DNA as Genetic Material

DNA is a polymer composed of nucleotides, each containing a nitrogenous base, a pentose sugar (deoxyribose), and a phosphate group. Multiple lines of evidence established DNA as the molecule of heredity.

• Nitrogenous Bases: Adenine (A), Guanine (G), Thymine (T), Cytosine (C).

• Chargaff’s Rules:

  • DNA base composition varies between species.

  • Within a species, %A = %T and %G = %C.

  • Purines (A, G) pair with pyrimidines (T, C), resulting in base pairs of uniform width.

Building the Structural Model of DNA

The structure of DNA was determined through scientific inquiry and collaboration among researchers.

• Rosalind Franklin: Used X-ray crystallography to reveal DNA’s helical structure, major and minor grooves, and uniform width.

• Watson and Crick: Used Franklin’s data and Chargaff’s rules to finalize the double helix model.

• Antiparallel Strands: Sugar-phosphate backbones run in opposite directions (5’ to 3’).

• Base Pairing: A pairs with T, C pairs with G via hydrogen bonds.

13.2 Many Proteins Work Together in DNA Replication & Repair

Base Pairing to a Template Strand

DNA replication relies on the complementarity of the two strands. Each strand serves as a template for the synthesis of a new strand, ensuring genetic fidelity.

• Semiconservative Replication: Each new DNA molecule contains one old and one new strand.

• Parent DNA: Unwinds to allow daughter strands to be built according to base-pairing rules.

DNA Replication: A Closer Look

Replication is a highly accurate and rapid process, involving many enzymes and proteins. The mechanism is similar in prokaryotes and eukaryotes, though more is known about bacterial replication.

• Origins of Replication:

  • Prokaryotes: Single origin on circular chromosome, two replication forks.

  • Eukaryotes: Multiple origins on linear chromosomes, many replication forks.

  • Replication bubbles form and forks move in opposite directions.

• Initiation Enzymes:

  • Helicase: Untwists and separates DNA strands at replication forks.

  • Single-strand binding proteins: Stabilize separated strands.

  • Topoisomerase: Relieves strain ahead of replication fork.

Synthesizing a New Strand

DNA polymerases can only add nucleotides to an existing chain, so replication begins with an RNA primer.

• Primase: Synthesizes short RNA primers (~5–10 nucleotides) complementary to the DNA template.

• DNA Polymerases:

  • Multiple types; catalyze elongation at replication fork.

  • Add nucleotides to the 3′ end of the growing strand.

  • Require RNA primer and DNA template.

  • Proofread and ensure correct base-pairing.

  • Elongation rate: ~500 nucleotides/sec (bacteria), ~50 nucleotides/sec (humans).

  • Form phosphodiester bonds via dehydration synthesis.

• RNA Primer Removal: Replaced by DNA; gaps joined by DNA ligase.

Antiparallel Elongation

DNA strands are synthesized in opposite directions due to the antiparallel nature of the double helix.

• Leading Strand: Synthesized continuously toward the replication fork; requires one primer.

• Lagging Strand: Synthesized discontinuously away from the fork in short segments called Okazaki fragments; multiple primers required.

• DNA Ligase: Joins Okazaki fragments to form a continuous strand.

Proofreading and Repairing DNA

Accurate DNA replication is essential for organismal survival. Multiple mechanisms ensure fidelity and repair damage.

• Proofreading: DNA polymerases correct errors during replication (error rate: 1 in 10 billion).

• Mismatch Repair: Other enzymes scan DNA post-replication to fix mismatched base pairs.

• DNA Damage: Caused by chemicals, radiation, or spontaneous changes.

• Nuclease: Cuts out damaged DNA; excision repair replaces with correct bases.

• Nucleotide Excision Repair: Removes and replaces damaged DNA, e.g., repairs UV-induced damage in skin cells.

Replicating the Ends of DNA Molecules

Linear chromosomes pose a challenge for replication at their ends. Specialized structures and enzymes address this issue.

• Telomeres: Repetitive nucleotide sequences at chromosome ends (e.g., TTAAGGG repeated 100–1,000 times); protect genes from shortening.

• Telomeric DNA: Acts as a buffer zone; does not prevent shortening but postpones it.

• Telomerase: Enzyme that lengthens telomeres in germ cells; not active in most somatic cells but active in some cancer cells, enabling their immortality.

• Telomere Shortening: Proposed to be linked to aging; telomerase is a target for cancer therapies.

Key Terms and Definitions

• DNA (Deoxyribonucleic Acid): The molecule that carries genetic information.

• Nucleotide: The building block of DNA, consisting of a nitrogenous base, a sugar, and a phosphate group.

• Helicase: Enzyme that unwinds DNA.

• DNA Polymerase: Enzyme that synthesizes new DNA strands.

• Okazaki Fragments: Short DNA segments synthesized on the lagging strand.

• Telomere: Protective DNA sequence at chromosome ends.

• Telomerase: Enzyme that extends telomeres.

Example: DNA Replication Process

• Replication begins at origins, DNA unwinds, and enzymes synthesize new strands using base-pairing rules.

• Leading strand is synthesized continuously; lagging strand is synthesized in fragments.

• Proofreading and repair mechanisms ensure high fidelity.

DNA Replication Equation

The formation of a phosphodiester bond during DNA synthesis:

Where dNTP is a deoxyribonucleotide triphosphate and PPi is pyrophosphate.

Comparison Table: Leading vs. Lagging Strand

Additional info: Telomerase activity is a focus of cancer research due to its role in cellular immortality. DNA repair mechanisms are crucial for preventing mutations that can lead to disease.