Lecture 7

Structure of DNA

  • DNA structure includes major and minor grooves, which are crucial for the interaction with histones.

  • Histones are proteins around which DNA is wrapped, enabling DNA compression.

SMC Proteins

  • SMCs (Structural Maintenance of Chromosomes) help compress and maintain DNA structure.

  • Important regions of SMC proteins:

    • DNA binding domain for interaction with DNA

    • Energy domain to induce compression.

  • SMCs function in both prokaryotes and eukaryotes, with or without histones.

  • They assist in the compression during the cell cycle.

Chromatin Structure

  • Chromatin comprises DNA wrapped around histones, requiring multiple proteins, including SMCs and topoisomerases.

  • Topoisomerases relieve pressure during DNA compression by cutting and reannealing DNA.

Core Histones

  • Core histones: H2A, H2B, H3, H4, and variant H1.

  • Core histones assist in the packaging of DNA, with an abundance of lysines and arginines providing a strong positive charge.

  • Positive charges neutralize the negative charge of DNA, facilitating stable interactions.

Histone Interactions

  • H2A binds to H2B and H3 binds to H4, forming heterodimers crucial for DNA binding.

  • Binding occurs at the minor groove on the DNA's sugar-phosphate backbone, not with the nitrogenous bases.

  • DNA flexibility influenced by AT (adenine-thymine) pairs allows wrapping around histones more effectively.

Nucleosome Structure

  • The nucleosome consists of segments of DNA (approximately 47 base pairs) wrapped around core histones.

  • The structure is often visualized as "beads on a string"; beads represent nucleosomes, and the string represents unbound DNA.

Histone Tails and Modifications

  • Histones have N-terminal tails that extend from the nucleosome and are sites for molecular modifications (e.g., acetylation, phosphorylation).

  • Modifications impact gene expression; for instance:

    • Acetylation opens chromatin, promoting gene expression.

    • Deacetylation condenses chromatin, repressing transcription.

Roles of Different Histones

  • H1 acts as a linker histone, providing additional compression and protecting more DNA (approximately 68 base pairs) compared to the core nucleosome.

  • Overall, core histones contribute to the structural integrity and tight packaging of DNA in the nucleus.

DNA Accessibility Solutions

  • Chromatin remodeling is vital for allowing gene access, involving:

    • Repositioning of histones to expose DNA regions.

    • Ejecting or replacing histones to modify DNA accessibility without drastically changing the overall compression.

Histone Variants and Their Functions

  • Histone variants (e.g., H2AX, H3.3) offer different functions and properties compared to standard histones.

  • Such variants can enhance or alter nucleosome functionality, impacting processes like DNA repair and transcription regulation.

The Histone Code and Epigenetics

  • The histone code refers to the pattern of modifications that dictate transcriptional activation or repression.

  • Reader complexes interpret histone modifications, influencing transcription factors and other proteins involved in gene regulation.

  • Epigenetic modifications from histones can be inherited and impact gene expression across generations without altering the DNA sequence.

Example of Histone Variant

  • H2AX: A variant of the core histone H2A, H2AX is essential for DNA repair processes. It becomes phosphorylated at sites of DNA double-strand breaks, serving as a signal for the recruitment of DNA repair proteins, thus playing a critical role in maintaining genomic stability.