Nuclear Envelope Overview

Nuclear Envelope

• A double-layered membrane complex surrounding the nucleus in eukaryotic cells
• Physically separates the nucleus from the cytoplasm, keeping DNA and chromatin inside
• Separates mRNA synthesis (in nucleus) from protein synthesis (in cytoplasm) to regulate gene expression

Outer Nuclear Membrane

• 7-8 nm thick
• Connected to the rough endoplasmic reticulum (ER)
• Contains ribosomes

Inner Nuclear Membrane

• 7-8 nm thick
• Contains specific proteins that connect to chromatin and the nuclear lamina

Perinuclear Space

• 10-30 nm wide
• Fluid-filled space between the inner and outer nuclear membranes
• Continuation of the ER lumen

Nuclear Pore Complex (NPC)

• Large protein complex forming a channel in the nuclear envelope
• Composed of proteins called nucleoporins (Nups)
• Facilitates communication between the nucleus and the cytoplasm
• Handles the exchange of macromolecules like proteins and RNA

Transport Through NPCs

• Small molecules and ions move passively
• Macromolecules require active transport with nuclear transport receptors
• Importin β: Transports molecules into the nucleus
• Exportin: Transports molecules out of the nucleus

Nuclear Lamina

• Located beneath the inner nuclear membrane
• Composed of proteins called nuclear lamins
• Forms a meshwork that provides structural support for the nucleus
• Involved in various nuclear processes, including DNA replication, transcription, and cell cycle regulation

Types of Lamins

• A-type lamins: Lamin A and C, encoded by the LMNA gene
• B-type lamins: Encoded by LMNB1 and LMNB2

Laminopathies

• Genetic disorders caused by mutations in lamin or lamina-interacting protein genes
• Due to disruptions in the nuclear lamina's ability to support the nucleus

Emery-Dreifuss Muscular Dystrophy

• An example of a laminopathy
• Caused by mutations in the LINC/emerin/lamin protein complex
• Symptoms include chronic joint stiffness, progressive muscle weakness, and cardiac issues in adulthood

Emerin

• An integral protein of the inner nuclear membrane
• Interacts with the nuclear lamina
• Organizes the nuclear membrane during cell division
• Stabilizes the nuclear membrane against mechanical stress

LINC Complex

• Connects the nuclear lamina to the cytoskeleton
• Positions the nucleus within the cell
• Coordinates nuclear and cytoplasmic activities
• Made up of Nesprin and SUN proteins in mammals

Nucleoplasm

• Gel-like substance inside the nucleus
• Contains chromatin, the nucleolus, and various proteins and nucleic acids
• Includes nucleoproteins (non-histones and histones) and nucleic acids (DNA and RNA)

Non-Histone Proteins

• Small, acidic proteins
• Include enzymes like DNA polymerase and RNA polymerase

Histone Proteins

• Basic proteins containing arginine, lysine, and histidine
• Positively charged
• Bind to DNA through ionic bonds for DNA packaging
• Can be modified (e.g., methylation and acetylation)

Chromatin

• A complex of DNA and nucleoproteins
• The packed form of DNA found in eukaryotic cells

Nucleosome

• The basic unit of chromatin
• Contains 8 histones (H2A, H2B, H3, H4) and 147 nucleotides of DNA wrapped around the histone octamer 1.65 times
• 60 nucleotides of linker DNA connect nucleosomes
• Histone H1 binds to linker DNA, forming a chromatosome

Types of Chromatin: Euchromatin

• Loosely packed
• Actively involved in gene expression
• Found in the nuclear interior

Types of Chromatin: Heterochromatin

• Tightly packed
• Genetically inactive
• Found near the nuclear periphery and associated with telomeres and centromeres

Constitutive Heterochromatin

• Contains repetitive, genetically inactive DNA
• Found in specific chromosomes (e.g., chromosomes 1, 9, 16, 19, and Y)
• Stable during development

Facultative Heterochromatin

• Becomes heterochromatic in specific cells or tissues
• Example: The inactive X chromosome in female somatic cells (Barr body)
• Reversible and can become transcriptionally active

Features of Heterochromatin

• DNA Methylation: Cytosine bases are methylated
• Histone Acetylation: Generally hypoacetylated (fewer acetyl groups), resulting in tight packing and gene silencing
• No recombination

Functions of Heterochromatin

• Centromere function
• Nuclear domain organization
• Gene repression (epigenetic regulation)

Metaphase Chromosome

• The condensed form of DNA during cell division
• Composed of two sister chromatids joined at the centromere
• A complex of DNA and proteins, including condensins and cohesins

Sister Chromatids

• Identical copies of a chromosome formed during DNA replication (S phase)
• Remain attached until anaphase of mitosis

Centromere

• Region on the chromosome where kinetochores attach
• Contains specialized chromatin and proteins
• Important for accurate chromosome segregation during cell division

CEN DNA

• The specific DNA sequence at the centromere

Kinetochore

• Multiprotein complex that attaches sister chromatids to the mitotic spindle
• Essential for chromosome segregation

Satellites

• Tandemly repeated DNA sequences in genetically inactive heterochromatin regions
• Often associated with secondary constrictions on acrocentric chromosomes

Secondary Constriction

• A narrowing on a chromosome, sometimes associated with satellites

Specialized Chromosome Features

• Nucleolus Organizing Regions (NOR): Regions on chromosomes that form the nucleolus
• Telomeres: Protective ends of linear chromosomes that prevent end-to-end fusions
  • Consist of repeated nucleotide sequences (e.g., TTAGGG in humans)
  • Function: "counting mechanism" for cellular aging and chromosomal stability
• Telomerase: Enzyme that maintains telomere length
  • Active in stem cells and embryonic cells
  • Has low activity in somatic cells
  • Overactive in cancer cells