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Pushing proteins off DNA - how do helicases unwind protein-coated DNA?

Funder: UK Research and InnovationProject code: BB/P001610/1
Funded under: BBSRC Funder Contribution: 341,469 GBP
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Pushing proteins off DNA - how do helicases unwind protein-coated DNA?

Description

DNA encodes all the genetic information needed to act as a blueprint for life. This blueprint, though, needs to be converted ultimately into the building blocks of a cell. However, the information that DNA stores is buried deep within the structure of this molecule and can only be accessed by stripping apart the two strands that constitute DNA, so-called unwinding. This critical function is performed by enzymes called helicases that are tiny nanomotors that ratchet along DNA, separating the two DNA strands as they go. All organisms have a variety of different helicases and defects in just one type of helicase can result in catastrophe for a cell, potentially causing lethality or debilitating mutations within genes. The central importance of helicases in maintaining the viability of all cells and in passing the genetic blueprint from one generation to the next has been known for decades. Recently we have also come to appreciate that helicases face a particular problem when attempting to unwind DNA. DNA is coated in a wide variety of different proteins inside cells. These proteins play important roles in packaging DNA, reading the genetic blueprint and coordinating the movement of chromosomes inside cells. Unfortunately we now know that these bound proteins also present problems to helicases since any proteins bound to the DNA must also be pushed off to allow separation of the two DNA strands by a helicase. However, we know very little about how helicases displace proteins bound to the nucleic acid. We have been studying a helicase called Rep that plays an important role in copying of the genetic blueprint by displacing proteins that are bound to DNA. Our preliminary work has discovered that removal of part of this helicase activates DNA unwinding but at the same time inhibits displacement of proteins from the DNA. This discovery is important because it shows that displacement of proteins from DNA must involve something more than the helicase merely ratcheting along the DNA. This helicase has therefore evolved specific features to help push proteins off DNA although currently we do not understand what these features are. We aim to investigate how this helicase displaces proteins from DNA by using a combination of different molecular tools to investigate the properties of Rep and versions of this helicase that have increased or decreased abilities to push proteins off DNA. This work will cast light on how this important class of enzyme deals with the vast array of proteins that coat DNA. This problem is one that all organisms must face and so our findings will help us to understand how DNA is maintained effectively inside cells and, just as importantly, how things might go wrong. Mistakes made by helicases can result in very harmful rearrangements within the genetic code, contributing to genetic disease, and so our proposed work will shed light on potential sources of corruption of the genetic code. Conversely, this work may also reveal new ways of deliberately inhibiting helicases. Such inhibitors have potential uses as antiviral, antibacterial and anticancer compounds since helicases are so important for survival.

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