The Cause of Bloom Syndrome

Tommy was a full-term baby but weighed only 4.5 pounds (2 kg) at birth. At about 9 months of age, an unusual and persistent rash appeared on his face, and he frequently caught colds and infections. The illnesses caused no serious problems; so his parents were not concerned. Throughout childhood, Tommy remained small; by age 18, he was only 4 feet 6 inches (137 cm) in height.

Tommy's first major health problem arose shortly after he turned 22—he was diagnosed with intestinal cancer. The tumor was surgically removed but additional, unrelated tumors appeared spontaneously over the next 10 years. Their appearance startled Tommy's doctors; the chance of multiple, independent cancers arising in the same person is generally remote. The propensity of Tommy's cells to become cancerous hinted at a high mutation rate in his genes. Indeed, when pathologists studied Tommy's chromosomes, they observed a wide range of abnormalities. Tommy had inherited Bloom syndrome.

Bloom syndrome is a rare autosomal recessive condition characterized by short stature, a facial rash induced by sun exposure, a small narrow head, and a predisposition to cancers of all types. The disorder is extremely rare; only several hundred cases have been reported worldwide. Cells from persons with Bloom syndrome exhibit excessive mutations in all genes, and numerous gaps and breaks occur in chromosomes that lead to extensive genetic exchange in cell division. Rates of DNA synthesis are retarded.

The characteristics of Bloom syndrome suggest that its underlying cause is a defect in DNA replication. In 1995, researchers at the New York Blood Center traced Bloom syndrome to a gene on chromosome 15 that encodes an enzyme called DNA helicase. A variety of helicase enzymes are responsible for unwinding double-stranded DNA during replication and repair. The cells of a person with Bloom syndrome carry two mutated copies of the gene and possess little or no activity for a particular helicase. Normal DNA replication is disrupted, leading to chromosome breaks and numerous mutations. The genetic damage resulting from faulty DNA replication leads to tumors. It is not yet clear whether the basic defect in DNA synthesis is associated with replication or DNA repair or both.

Rapid and accurate DNA replication is fundamental to normal cell function and health. Replication is a complex process in which dozens of proteins, enzymes, and DNA structures take part; a single defective component, such as DNA helicase, can disrupt the whole process.

This chapter deals with DNA replication, the process whereby a cell doubles its DNA before division. We begin with the basic mechanism of replication that emerged from the Watson and Crick structure of DNA. We then examine several different modes of replication, the requirements of replication, and the universal direction of DNA synthesis. We examine the enzymes and proteins that participate in the process and conclude the chapter by considering the molecular details of recombination, which is closely related to replication and is essential for the segregation of homologous chromosomes in meiosis, production of genetic variation, and for DNA repair. More information about the symptoms and genetics of Bloom syndrome

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