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A Novel Double-Stranded DNA Structure Identified

Double-stranded DNA has often been described as a right-handed helical structure, known as B-DNA. To perform its multiple functions, double-stranded DNA has multiple structures depending on conditions. For example, the melted DNA bubble forms during transcription elongation and the left-handed helical Z-DNA forms hypothetically during transcriptional regulations.

Scientists have been proposing a novel form of double-stranded since 1996. Referred to as ‘S-DNA’, it is produced from stretching the B-form DNA beyond a certain ‘transition force’ of around 65 pN to approximately 1.7-fold in length (termed as DNA overstretching transition). Its existence has sparked a 16-year scientific debate since it was proposed, as many other evidences suggested that DNA overstretching transition was merely a force-induced DNA melting transition, leading to peeled-apart single-stranded DNA.

At (NUS), the research was led by , from the Department of Physics, Faculty of Science and Mechanobiology Institute, Singapore. It succeeded in demonstrating the intricacies of the DNA mechanics in highly sensitive single-DNA stretching experiments.

Assoc Prof Yan and his team found that DNA overstretching may involve two transitions that are distinct in their transition kinetics, namely, a slower hysteretic peeling transition to peeled-apart single-stranded DNA and a faster non-hysteretic transition to an unknown DNA structure. However, whether the unknown DNA structure produced from the non-hysteretic transition is the S-DNA or two single-stranded through inside-DNA-melting, remains a question.

Their findings were published in Nucleic Acids Research.

In another recent work published in Proceedings of the National Academy of Sciences, Assoc Prof Yan and co-researchers examined the thermodynamics associated with the two transitions. They found that the non-hysteretic transition was associated with a small negative entropy change, in contrast to the large positive entropy change found during the hysteretic peeling transition. This result strongly favors DNA re-arrangement into a highly ordered, non-melted state during the non-hyteretic transition. They also demonstrated that the selection between the two transitions was dependent on DNA base-pair stability and could be represented in a multi-dimensional phase diagram.

Their results not only brought clarity to the scientific debate of whether S-DNA exists, but also provided important insights to the possible structures and functions of the mysterious S-DNA.

Given its elongated structure, the S-DNA may be a potential binding substrate for DNA intercalators, including those used in chemotherapeutic treatment to inhibit in rapidly growing cancer cells. In cells, many DNA-binding proteins utilize side chain intercalation to distort the . Therefore, the S-DNA may also be a potential binding substrate for these proteins that occur in living organisms.


National University of Singapore