HLTF的古老HIRAN结构域结合3'端DNA以驱动复制叉逆转。
HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal.
作者信息
Kile Andrew C, Chavez Diana A, Bacal Julien, Eldirany Sherif, Korzhnev Dmitry M, Bezsonova Irina, Eichman Brandt F, Cimprich Karlene A
机构信息
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
出版信息
Mol Cell. 2015 Jun 18;58(6):1090-100. doi: 10.1016/j.molcel.2015.05.013. Epub 2015 Jun 4.
Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA damage responses in humans is the Rad5-related DNA translocase, HLTF. Here, we present biochemical and structural evidence that the HIRAN domain, an ancient and conserved domain found in HLTF and other DNA processing proteins, is a modified oligonucleotide/oligosaccharide (OB) fold that binds to 3' ssDNA ends. We demonstrate that the HIRAN domain promotes HLTF-dependent fork reversal in vitro through its interaction with 3' ssDNA ends found at forks. Finally, we show that HLTF restrains replication fork progression in cells in a HIRAN-dependent manner. These findings establish a mechanism of HLTF-mediated fork reversal and provide insight into the requirement for distinct fork remodeling activities in the cell.
停滞的复制叉对细胞来说是一个关键问题，因为它们会导致复杂的基因组重排，而这些重排是细胞死亡和疾病的基础。诸如DNA损伤耐受和复制叉逆转等过程可保护停滞的复制叉免受这些事件的影响。人类这些DNA损伤反应的核心介质是Rad5相关的DNA转位酶HLTF。在这里，我们提供了生化和结构证据，表明HIRAN结构域是一种在HLTF和其他DNA加工蛋白中发现的古老且保守的结构域，它是一种与3'单链DNA末端结合的修饰寡核苷酸/寡糖（OB）折叠。我们证明，HIRAN结构域通过与复制叉处的3'单链DNA末端相互作用，在体外促进HLTF依赖的复制叉逆转。最后，我们表明HLTF以HIRAN依赖的方式抑制细胞中的复制叉进展。这些发现建立了HLTF介导的复制叉逆转机制，并为细胞中不同复制叉重塑活动的需求提供了见解。
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