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OVERVIEW

The nucleus is often represented as a relatively empty structure, containing only deoxyribonucleic acid (DNA) being replicated and transcribed along with a few accessory molecules to help in the process. To the contrary, the nucleus is actually a highly organized, membrane-bound structure that is literally filled with proteins, nucleotides, carbohydrates, and lipids with multiple functions. Various proteins are involved, along with the nuclear membrane, in the organization of chromosomes, which also helps to regulate the processes of DNA replication and transcription, and, subsequently, protein synthesis. Other proteins directly influence the expression of genes via direct interactions with specific nucleotide sequences. Post-translational modifications affect both protein function and direct particular proteins to intracellular and/or extracellular destinations.

STRUCTURE OF THE NUCLEUS

The nucleus is surrounded by a double membrane called the nuclear membrane (also known as the nuclear envelope), with the outer layer being continuous with the endoplasmic reticulum (ER) in the cytoplasm and, like the ER, containing ribosomes and newly synthesized proteins. The inner and outer nuclear membranes are also continuous at the sites of nuclear pores. Approximately 2000 nuclear pores are contained within the nuclear membrane, and each pore can allow movement of about 1000 molecules in and out of the nucleus per second. These nuclear pores, composed of proteins called nucleoporins, are directly analogous to the membrane channels discussed in Chapter 8 and transport several types of molecules, including ribonucleic acid (RNA) and ribosomes, proteins, carbohydrates, and lipids. Smaller molecules and ions pass through the nuclear pore by simple diffusion, but larger proteins and RNA molecules are blocked by a spoke-like gate inside the channel and must be actively assisted by carrier proteins called “importins” or “exportins” by a process that requires two guanosine triphosphate (GTP) molecules. Each type of RNA molecule [messenger RNA (mRNA) and transfer RNA (tRNA)] that must be transported into the cytoplasm has an exportin and a specific amino acid (AA), nuclear export sequence, which directs them to a specialized nuclear pore for their selected transport out of the nucleus.

Leptomycins: Leptomycins A and B, originally developed as antifungal drugs, specifically alkylate an importin, which results in inhibition of the nuclear export of several RNAs and transcription regulators in cell cycle control. An additional leptomycin is an HIV-1 regulator which allows HIV to take over host protein synthesis. The leptomycins also stabilize p53, known to suppress tumor development/growth. Because of their cell cycle effects (see below), leptomycins are now being considered for cancer therapy.

HISTONES

The most important structure inside the nucleus is chromatin, consisting, in humans, of the 46 chromosomes and their associated proteins. These proteins enable not only efficient packing of over 12 billion nucleotides in human DNA, but also selective unwinding of these chromosomes to expose genes for DNA replication, DNA to RNA transcription and mRNA processing. Histones...

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