Mechanistic Biology of FAN1

以结构特异的方式水解DNA的能力是生命所必需的，但也是一个巨大的分子识别挑战。FANCD2/FANCI相关核酸酶(FAN1)是一种重要的结构特异性核酸酶，参与DNA链间交联的修复。它的突变与几种癌症和退行性疾病的关系说明了FAN1的重要性。FAN1可降解5‘端折叠结构，并使切割3个核苷酸形成双链体变钝，但其结构与其他未参与交联修复的5’端核酸酶完全不同。报道了FAN1-DNA络合物的两种结晶学结构。然而，它们在与DNA的结合方式(弯曲的或直的)、与一个DNA结合的蛋白质分子的数量等方面有很大的不同，因此提出了两种非常不同的FAN1作用模型。在这里，我们计划研究FAN1行动的机制生物学，以解决这一争论。

The ability to hydrolyse DNA in a structure specific manner isessential to life and yet presents a formidable molecular recognition challenge.FANCD2/FANCI-associated nuclease (FAN1) is an example of a vital structurespecificnuclease that is involved in repair of interstrand cross-links in DNA. Theassociation of its mutations with several cancers and degenerative diseasesillustrates the importance of FAN1. FAN1 hydrolyses 5' flap structures and bluntends cutting 3 nucleotides into a duplex, but has a completely different structureto other 5' nucleases not involved in cross-link repair. Two crystallographicstructures of the FAN1-DNA complexes have been reported. However, thesediffer considerably e.g., in binding mode to DNA (bent or straight), number ofprotein molecules bound to one DNA etc. and consequently two very differentmodels for FAN1 action have been proposed. Here we plan to investigate themechanistic biology of FAN1 action resolving this debate.