Understanding the details of cell-cycle regulation has had an impact on cancer research and has contributed to the development of new treatments. For instance, inactiva-tion of tumor-suppressor genes has been shown to play a role in the growth and division of cancer cells. The pro-teins encoded by these genes are used by the cell throughout several DNA-damage checkpoints. For in-stance, mutations in the breast cancer susceptibility gene 1 (BRCA-1) and breast cancer susceptibility gene 2 (BRCA-2) are associated with an increased risk for bilateral breast cancer. Both protein products of these tumor-suppressor genes–namely, BRCA-1 and BRCA-2 proteins–are directly involved in multiple cellular pro-cesses in response to DNA damage, including checkpoint activation, gene transcription, and repair of DNA double-strand breaks. Together with RAD-51 protein, which is involved in the homologous recombination and repair of DNA, they maintain stability of the human genome. The defective BRCA proteins are unable to interact with RAD-51. By screening patients for mutations in these genes, much earlier detection of cancer can be accomplished. It is also now known why in some individuals p53 mu-tations make their tumors resistant to radiotherapy. DNA damage caused by therapeutic radiation procedures is de-tected by DNA-damage checkpoints, which cause cancer cells to be arrested in the cell cycle. However, these cells will not die because of the absence of functional p53, which triggers apoptosis.
The Cell Nucleus  NUCLEAR COMPONENTS
FIGURE 3.5 • Structure of the nuclear envelope and its relationship to the rER. a. The nuclear wall consists of a double membrane envelope that surrounds the nucleus. The outer membrane is continuous with the membranes of the rER; thus, the perinuclear space communicates with the rER lumen. The inner membrane is adjacent to nuclear intermediate filaments that form the nuclear lamina. b. This electron micrograph, prepared by the quick-freeze deep-etch technique, shows the nucleus, the large spherical object, surrounded by the nuclear envelope. Note that the outer membrane possesses ribosomes and is continuous with the rER. 12,000. (Courtesy of Dr. John E. Heuser, Washington University School of Medicine.) membrane. It addition to its supporting or “nucleoskeletal” function, nuclear lamina is essential in many nuclear activities such as DNA replication, transcription, and gene regulation. If the membranous component of the nuclear envelope is disrupted by exposure to detergent, the nuclear lamina remains, and the nucleus retains its shape.
The major components of the lamina, as determined by biochemical isolation, are nuclear lamins, a specialized type of nuclear intermediate filament (see page 63), and laminassociated proteins. Nuclear lamina is essentially composed of lamin A and lamin C proteins that form intermediate filaments. These filaments are cross-linked into an orthogonal lattice (Fig. 3.6), which is attached mainly via lamin B protein to the inner nuclear membrane through its interactions with lamin receptors. The family of lamin receptors includes emerin (34 kilodaltons) that binds both lamin A and B, nurim (29 kilodaltons) that binds lamin A, and a 58-kilodalton lamin B receptor (LBR) that, as its name suggests, binds lamin B.
Unlike other cytoplasmic intermediate filaments, lamins disassemble during mitosis and reassemble when mitosis ends. The nuclear lamina appears to serve as scaffolding for chromatin, chromatin-associated proteins, nuclear pores, and the membranes of the nuclear envelope. In addition, it is involved in nuclear organization, cell-cycle regulation, differentiation, and gene expression.