A DNA repair interactome based on linear peptide motifs

存在于我们细胞中的DNA不断地以各种方式被破坏，因此，所有已知的生命形式都进化出了一套复杂的生化途径来检测和修复这种破坏，统称为DNA损伤反应。像所有的生物学途径一样，DNA损伤反应是由一系列蛋白质-蛋白质相互作用促进的，但DNA修复蛋白复合物的组装、拆卸和翻译后修饰调节的机制仍然知之甚少。为了解决这一问题，本项目旨在开发和优化生物信息学和蛋白质组学相结合的方法，以鉴定和表征依赖于保守的线性肽基序的DNA损伤反应蛋白中的新型蛋白质-蛋白质相互作用。通常长度小于30个氨基酸，肽基序被相互作用的伙伴识别和/或翻译后修饰。从历史上看，大多数旨在阐明蛋白质-蛋白质相互作用的研究都集中在蛋白质结构域之间的相互作用上，但近年来，许多相互作用都是由肽基序介导的。除了鉴定新的蛋白质-蛋白质相互作用外，该方法还具有将这些相互作用映射到其中一种蛋白质上的特定区域的潜力，并且如果已知基序中存在翻译后修饰，则可以深入了解这种相互作用是如何调节的。

DNA present in our cells is continually being damaged in various ways and accordingly all known forms of life have evolved a complex set of biochemical pathways to detect and repair such damage, collectively called the DNA damage response. Like all biological pathways, the DNA damage response is facilitated by a series of protein-protein interactions, but the mechanisms by which DNA repair protein complexes are assembled, disassembled and regulated by post-translational modifications are still poorly understood. To address this issue, this project aims to develop and optimize a combined bioinformatics and proteomics approach to identify and characterize novel protein-protein interactions in DNA damage response proteins relying on conserved linear peptide motifs. Typically less than thirty amino acids in length, peptide motifs are recognised and/or post translationally modified by interacting partners. Historically, most research aiming to elucidate protein-protein interactions has focused on the interaction between the structured domains of proteins but in recent years it has become apparent that many interactions are mediated by peptide motifs. In addition to identifying novel protein-protein interactions, this method has potential to map these interactions to a specific region on one of those proteins and to gain insight into how this interaction is regulated if post-translational modifications are known to be present in the motif.