DNA INVERTED REPEATS AND HUMAN DISEASE

John J. Bissler

The Children's Hospital Research Foundation, Cincinnati, Ohio

2. INTRODUCTION

Mutations in the genome can result in inherited as well as malignant diseases. Studying the different mechanisms causing mutation will lead to strategies that promote health by reducing the mutagenic potential. Governmental regulations governing use and disposal of some genotoxic substances, such as radioactive material, are such a strategy. Like external mutagenic agents, innate mechanisms of mutation also lead to human disease. Two

examples of innate mechanisms leading to mutation are deficiencies in DNA repair systems (1), and mutations that evade repair (2). The combined impact of innate and environmental mutagenesis over millennia has been to cause genetic variation and, as a result of natural selection, facilitate evolution.

The fidelity of the genetic code is particularly vulnerable to mutagenic mechanisms during replication. During cell cycle phases other than S-phase, DNA is compared to the complementary strand and, if needed, repaired. During replication of the genetic code, point and frameshift mutations can occur in the newly synthesized strand. Replication is a rapid process. One estimate is that replication occurs at a rate of 1,000 bp per second (3). The DNA replication rate (4) and fidelity varies depending on the template sequence (5-7). Certain template sequences are more prone to replication errors. In this review, I will focus on the inverted repeat and its mechanistic role in contribu