Mechanistic Biology of FAN1

FANCD 2/FANCI相关核酸酶（FAN 1）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联说明了FAN 1的重要性。FAN 1水解5'侧翼结构并将3个核苷酸平端切割成双链体，但与不参与交联修复的其他5'核酸酶具有完全不同的结构。FAN 1-DNA复合物的两种晶体学结构已被报道。然而，这些差异很大，例如，在与DNA结合模式（弯曲或直）中，许多蛋白质分子与一个DNA结合等，因此已经提出了FAN 1作用的两种非常不同的模型。在这里，我们计划调查FAN 1行动的机制生物学解决这一争论。

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.