6.3 Supercoiling and topological considerations

DNA supercoiling is a crucial aspect of nucleic acid structure, affecting how DNA twists and coils around itself. This higher-order organization impacts DNA's physical properties and biological functions, influencing everything from gene expression to chromosome structure.

Understanding supercoiling is key to grasping how DNA behaves in cells. It's not just about the double helix – it's about how that helix folds and twists in 3D space, affecting how genes are accessed and expressed.

DNA Supercoiling and Topology

Definition and Relationship to DNA Structure

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• Supercoiling refers to the higher-order coiling or twisting of the DNA double helix around itself, beyond the typical Watson-Crick base pairing and helical structure
• DNA supercoiling is a topological property that arises from the constraint of the two strands being intertwined and unable to separate completely
• Positive supercoiling occurs when the DNA is twisted in the same direction as the right-handed double helix, resulting in a more tightly wound structure (plectonemic supercoiling)
• Negative supercoiling occurs when the DNA is twisted in the opposite direction of the right-handed double helix, resulting in a more loosely wound or unwound structure (toroidal supercoiling)
• The degree and type of supercoiling can significantly influence the physical properties and biological functions of DNA molecules

Types and Effects of Supercoiling

• Positive supercoiling
  • Occurs when the DNA is overwound or twisted in the same direction as the right-handed double helix
  • Results in a more compact and tightly wound DNA structure
  • Can stabilize DNA secondary structures, such as cruciforms or Z-DNA, which may have regulatory roles in gene expression
• Negative supercoiling
  • Occurs when the DNA is underwound or twisted in the opposite direction of the right-handed double helix
  • Results in a more loosely wound or unwound DNA structure
  • Facilitates the unwinding of DNA strands, which is essential for processes such as replication, transcription, and recombination
• Effects on DNA properties and functions
  • Supercoiling affects the accessibility of DNA to proteins involved in DNA-related processes (transcription factors, polymerases, and regulatory proteins)
  • Changes in supercoiling can serve as a mechanism for regulating gene expression by altering the accessibility of promoter regions to the transcriptional machinery
  • Supercoiling plays a role in the formation and maintenance of chromosome structure, including the organization of topologically associating domains (TADs) and higher-order chromatin interactions

Linking Number, Twist, and Writhe

Definitions and Mathematical Relationship

• Linking number (Lk)
  • A topological property that describes the number of times one DNA strand crosses over the other in a closed-circular DNA molecule
  • Represents the sum of twist and writhe in a closed-circular DNA molecule
• Twist (Tw)
  • Refers to the number of helical turns or the winding of the DNA strands around each other in a particular topological state
  • Corresponds to the local winding of the DNA double helix
• Writhe (Wr)
  • Describes the number of times the DNA double helix crosses over itself in three-dimensional space, contributing to the overall supercoiling
  • Represents the global coiling or folding of the DNA molecule
• The mathematical relationship between linking number, twist, and writhe is defined as $Lk = Tw + Wr$, which is a fundamental equation in DNA topology

Changes in Linking Number and Topological States

• Changes in the linking number (ΔLk) can be achieved by altering either the twist or writhe of the DNA molecule, which results in different topological states or supercoiled conformations
• Positive changes in linking number (ΔLk > 0) lead to positive supercoiling, while negative changes in linking number (ΔLk < 0) lead to negative supercoiling
• Topoisomerases can change the linking number by introducing transient breaks in the DNA backbone, allowing for the interconversion between different topological states
• The relationship between linking number, twist, and writhe allows for the description and quantification of DNA supercoiling and its effects on DNA structure and function

Biological Significance of Supercoiling

DNA Packaging and Compaction

• DNA supercoiling plays a crucial role in the compact storage of genetic material within the cell, as it allows for the efficient packaging of the long DNA molecules into the limited space of the nucleus or nucleoid
• Negative supercoiling facilitates the unwinding of DNA strands, which is essential for processes such as replication, transcription, and recombination
• Positive supercoiling can help stabilize DNA secondary structures, such as cruciforms or Z-DNA, which may have regulatory roles in gene expression

Regulation of DNA-Related Processes

• The level of DNA supercoiling can influence the binding and activity of proteins involved in DNA-related processes, such as transcription factors, polymerases, and regulatory proteins
• Changes in DNA supercoiling can serve as a mechanism for regulating gene expression by altering the accessibility of promoter regions to the transcriptional machinery
• Supercoiling affects the formation and stability of DNA secondary structures (hairpins, cruciforms, Z-DNA), which can play a role in the regulation of gene expression and DNA replication

Chromosome Structure and Genome Organization

• DNA supercoiling is involved in the formation and maintenance of chromosome structure, including the organization of topologically associating domains (TADs) and higher-order chromatin interactions
• Supercoiling contributes to the compaction and segregation of chromosomes during cell division, ensuring the faithful transmission of genetic material to daughter cells
• Changes in DNA supercoiling can affect the local chromatin structure and influence the accessibility of DNA to regulatory proteins and chromatin remodeling factors

Topoisomerases and DNA Topology

Types and Functions of Topoisomerases

• Topoisomerases are enzymes that regulate DNA topology by introducing transient breaks in the DNA backbone, allowing for the relief of supercoiling and the interconversion between different topological states
• Type I topoisomerases (topoisomerase I)
  • Create single-strand breaks in the DNA and change the linking number in steps of one
  • Relax both positive and negative supercoils by allowing the rotation of the broken strand around the intact strand
  • Examples include bacterial topoisomerase I and eukaryotic topoisomerase I
• Type II topoisomerases (topoisomerase II)
  • Create double-strand breaks in the DNA and change the linking number in steps of two
  • Efficiently remove knots and tangles in the DNA by passing one double-stranded segment through another
  • Examples include bacterial gyrase and eukaryotic topoisomerase II

Topoisomerase Activity and Cellular Processes

• Topoisomerases are essential for maintaining the appropriate level of DNA supercoiling during processes such as replication, transcription, and chromosome segregation
• During DNA replication, topoisomerases relieve the positive supercoiling that accumulates ahead of the replication fork, allowing for the unwinding of the DNA strands
• Topoisomerases are required for the efficient progression of transcription by removing the positive supercoiling generated behind the transcribing RNA polymerase
• In chromosome segregation, topoisomerases help resolve the topological entanglements between sister chromatids, ensuring their proper separation during cell division

Topoisomerase Inhibitors and Therapeutic Applications

• Inhibition of topoisomerase activity can lead to the accumulation of supercoiling and the formation of DNA knots or catenanes, which can disrupt normal cellular processes and lead to genomic instability
• Some antibiotics (quinolones) and chemotherapeutic agents (etoposide, doxorubicin) target topoisomerases, exploiting their crucial role in DNA topology to induce DNA damage and cell death in bacterial or cancer cells, respectively
• Topoisomerase inhibitors can trap the enzyme-DNA complex, leading to the formation of double-strand breaks and the activation of DNA damage response pathways
• The selective targeting of topoisomerases in rapidly dividing cells, such as cancer cells, makes topoisomerase inhibitors effective anti-cancer agents in chemotherapy regimens