Structure of HIRAN Domain of Human HLTF Bound to Duplex DNA Provides Structural Basis for DNA Unwinding to Initiate Replication Fork Regression
Structure of HIRAN Domain of Human HLTF Bound to Duplex DNA Provides Structural Basis for DNA Unwinding to Initiate Replication Fork Regression
复制标题
与双链 DNA 结合的人类 HLTF HIRAN 结构域的结构为 DNA 解旋以启动复制叉回归提供了结构基础
DOI：
10.1093/jb/mvaa008
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hiroshi Hashimoto
中科院分区：
文献类型：
--
作者：
Asami Hishiki;Mamoru Sato;Hiroshi Hashimoto
复制分叉回归是一种通过各种复制应激（如DNA损伤）来挽救停滞分叉的机制。解旋酶样转录因子是一种SNF2转位酶，在叉回归中起核心作用，其n端结构域hiiran （HIP116和rad5n端）结合单链DNA的3 ' -羟基基团。此外，HIRAN被认为结合双链DNA （dsDNA）并参与分叉回归中的链分离，然而HIRAN结合dsDNA和链分离机制的结构基础尚不清楚。在这里，我们报道了HIRAN与双链DNA结合的晶体结构。该结构揭示了HIRAN结合DNA的3 ' -羟基，并意外地解开了双链的三个核碱基。ph -142参与了dsDNA的结合和链分离。此外，该结构揭示了HIRAN对嘌呤碱基的序列独立识别机制，其中then -糖苷键采用同构构象。我们的研究结果表明，HIRAN通过从亲本模板中分离子链直接参与叉回归。
Replication fork regression is a mechanism to rescue a stalled fork by various replication stresses, such as DNA lesions. Helicase-like transcription factor, a SNF2 translocase, plays a central role in the fork regression and its N-terminal domain, HIRAN (HIP116 andRad5N-terminal), binds the 3’-hydroxy group of single-stranded DNA. Furthermore, HIRAN is supposed to bind double-stranded DNA (dsDNA) and involved in strand separation in the fork regression, whereas structural basis for mechanisms underlying dsDNA binding and strand separation by HIRAN are still unclear. Here, we report the crystal structure of HIRAN bound to duplex DNA. The structure reveals that HIRAN binds the 3’-hydroxy group of DNA and unexpectedly unwinds three nucleobases of the duplex. Phe-142 is involved in the dsDNA binding and the strand separation. In addition, the structure unravels the mechanism underlying sequence-independent recognition for purine bases by HIRAN, where theN-glycosidic bond adoptssynconformation. Our findings indicate direct involvement of HIRAN in the fork regression by separating of the daughter strand from the parental template.