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 that genetic information is reproduced in all cells.

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.

• 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, following base-pairing rules.

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

• Parent Molecule: Unwinds to allow daughter strands to form.

DNA Replication: A Closer Look

DNA replication is a highly accurate and rapid process, involving many enzymes and proteins.

• Replication Origins:

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

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

  • Replication 'bubbles' form and expand as DNA is unwound.

• Key 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 synthesize new DNA by adding nucleotides to an existing chain, using a template strand.

• RNA Primers: Short RNA sequences synthesized by primase to provide a starting point.

• DNA Polymerases:

  • Add nucleotides to the 3′ end of the primer.

  • Require a template strand and primer.

  • Proofread and ensure correct base pairing.

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

  • Form phosphodiester bonds via dehydration synthesis.

• Primer Removal: RNA primers are degraded and replaced with DNA.

Antiparallel Elongation

DNA strands are synthesized in an antiparallel manner, leading to distinct mechanisms for leading and lagging strands.

• 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.

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

Proofreading and Repairing DNA

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

• Proofreading: DNA polymerases correct errors during replication.

• Mismatch Repair: Other enzymes scan and correct mismatched base pairs missed by polymerases.

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

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

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

Replicating the Ends of DNA Molecules

Linear DNA presents unique challenges during replication, particularly at chromosome ends.

• Telomeres: Special nucleotide sequences at chromosome ends; protect genes from erosion.

• Telomeric DNA: Consists of repeated sequences (e.g., TTAAGGG, repeated 100–1,000 times).

• Function: Acts as a buffer zone; postpones gene loss but does not prevent shortening.

• Telomerase: Enzyme that lengthens telomeres in germ cells; not active in most somatic cells.

• Cancer Connection: Telomerase is active in some cancer cells, enabling their 'immortalization'; a target for cancer therapies.

Example: DNA Replication in Eukaryotes

During cell division, eukaryotic cells initiate DNA replication at multiple origins, forming replication bubbles. Enzymes coordinate to unwind DNA, synthesize new strands, and repair errors, ensuring faithful transmission of genetic information.

Key Terms and Definitions

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

• Nucleotide: The basic unit 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 Fragment: Short DNA segment synthesized on the lagging strand.

• Telomere: Protective DNA sequence at chromosome ends.

• Telomerase: Enzyme that extends telomeres.

DNA Replication: Summary Table

Key Equations

• Phosphodiester Bond Formation:

• Chargaff's Rule:

Additional info: Telomere shortening is associated with cellular aging, and telomerase activity is a focus of cancer research and potential therapies.