The halting arrival of left-handed Z-DNA C. E. Gagna, 1,2 W. C. Lambert 1 1 University of Medicine and Dentistry of New Jersey Medical-School, Newark, New Jersey, USA; 2 New York Institute of Technology, Old Westbury, New York, USA Summary Forty-nine years ago Watson and Crick proposed a double-stranded (ds-) model for DNA. This double helix has become an icon of molecular biology. Twenty-six years later, Rich accidently discovered Z-DNA, an exotic left-handed nucleic acid. For many years thereafter, this left-handed DNA was thought to be an artifact. DNA is no longer looked upon as a static molecule but rather an extremely dynamic structure in which different conformations are in equilibrium with each other. Many researchers have spent the last two decades characterizing this novel left-handed DNA structure. Now many investigators are beginning to accept the possibility that this novel ds-DNA conformation may play a significant in vivo role within eukaryotic and prokaryotic cells. However, more research needs to be performed before it is absolutely accepted by all in the scientific community. ª 2003 Elsevier Science Ltd. All rights reserved. INTRODUCTION In 1953, Watson and Crick (1) proposed a double-helix conformation for DNA. Their journal article publication was only 900 words long, but it described the three-di- mensional geometry of DNA. This finding helped usher in a scientific revolution. Their discovery ranks with Darwin’s theory of evolution and Mendel’s laws of in- heritance in its contribution to society’s understanding of biological processes. Of all the biological molecules, DNA garners the most public attention, since it is critical to the phenomenon of heredity and the transfer of ge- netically determined features from one generation to the next. For a long time after the discovery of the double- stranded (ds-) right-handed B-DNA molecule, many sci- entists believed that it was a quiescent molecule, but we now know that DNA is polymorphic, with such exotic structures as left-handed Z-DNA (Fig. 1) (2). Under cer- tain conditions right-handed ds-B-DNA can take on other forms: the A-DNA form when it is dehydrated, the C-DNA form in certain solvents. As relative humidity is increased, DNA undergoes a helical transition from the shorter stout A-DNA, with it base pairs inclined with respect to the helix axis, to the longer slender B-DNA, with its base pairs perpendicular to the helix axis. In recent years most scientists and medical professionals have been shocked to learn that the standard textbook version of ds-DNA they studied has been challenged. The majority of natural DNA molecules are in the right- handed helical conformation, viz., ds-B-DNA, which spirals to the right (3). About 20 other slightly different variations of the right-handed helical form of ds-DNA exists, such as A-DNA, C-DNA, and D-DNA (Fig. 2) (4–6). DNA should also be considered in terms of having a tertiary structure. Compared to the completely extended linear form of highly purified right-handed ds-B-DNA, the DNA in a human chromosome is folded in such a manner that it is compacted about 8000-fold in length. DNA encodes biological information in two ways. First, via the linear sequence of base pairs, for the production of proteins. Second, through the particular shape of the 418 Medical Hypotheses (2003) 60(3), 418–423 ª 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-9877(02)00418-8 Received 11 February 2002 Accepted 30 August 2002 Correspondence to: Dr C.E. Gagna FAIC, CChem FRSC, ChE, Assistant Professor, NYIT, New York College of Osteopathic Medicine #2, Room 362, Old Westbury, NY 11568-8000, USA. Phone: +516-686-3877; Fax: +201-224-7364; E-mail: dr.c.gagna@att.net