Sergei Mirkin, Tufts University
Tuesday, May 10, 2016 - 11:00am
From unorthodox DNA structures to genome instability and human disease
Roughly 30 years ago, we have discovered an unusual DNA structure called H-DNA, which was three-stranded at its core. This was, in fact, the first multistranded structure ever detected in natural DNA. This breakthrough was soon followed by the discovery of four-stranded G-quartet DNA made in the laboratories of Walter Gilbert, Aaron Klug and Thomas Cech. Altogether, these early studies triggered a worldwide interest in alternative DNA structures and their possible biological roles. Numerous in vitro studies conducted by us and others have shown that these structures can block DNA replication and transcription at their elongation steps. Paradoxically, DNA replication and transcription appeared to contribute to the structure formation in the first place by unwinding duplex DNA. This lead us to formulate the concept of “suicidal DNA sequences” stipulating that DNA replication triggers the formation of unorthodox DNA structures that, in turn, stall subsequent replication fork progression. The same is also true for genomic DNA in living cells: unorthodox DNA structures are formed only transiently, primarily during DNA replication and sometimes during transcription, and they inhibit these genetic processes that lead to their formation. We then have come to realize that replication fork stalling at structure-prone DNA sequences is one of the main sources of genome instability, leading to many hereditary disorders in humans, chromosomal rearrangements in cancer, etc. This concept has since been confirmed in many labs worldwide. Furthermore, these structure-prone sequences appear to account for the inactivation of their carrier genes, contributing to the disease phenotype. With this understanding in mind, we are currently developing mammalian experimental systems to study the mechanisms of genome instability and gene repression caused by structure-prone DNA sequences. In the future, these systems could be used to conduct a search for drugs that reverse adverse effects of structure-prone sequences, which in the long run, could lead to the development of therapeutics against these debilitating genetics diseases.