Structural basis for the multi-activity factor Rad5 in replication stress tolerance

Miaomiao Shen, Nalini Dhingra, Quan Wang, Chen Cheng, Songbiao Zhu, Xiaolin Tian, Jun Yu, Xiaoxin Gong, Xuzhichao Li, Hongwei Zhang, Xin Xu, Liting Zhai, Min Xie, Ying Gao, Haiteng Deng, Yongning He, Hengyao Niu, Xiaolan Zhao and Song Xiang ()
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Miaomiao Shen: Tianjin Medical University
Nalini Dhingra: Memorial Sloan Kettering Cancer Center
Quan Wang: Indiana University Bloomington
Chen Cheng: Chinese Academy of Sciences
Songbiao Zhu: Tsinghua University
Xiaolin Tian: Tsinghua University
Jun Yu: Chinese Academy of Sciences
Xiaoxin Gong: Tianjin Medical University
Xuzhichao Li: Tianjin Medical University
Hongwei Zhang: Chinese Academy of Sciences
Xin Xu: Tianjin Medical University
Liting Zhai: Chinese Academy of Sciences
Min Xie: Chinese Academy of Sciences
Ying Gao: Chinese Academy of Sciences
Haiteng Deng: Tsinghua University
Yongning He: Chinese Academy of Sciences
Hengyao Niu: Indiana University Bloomington
Xiaolan Zhao: Memorial Sloan Kettering Cancer Center
Song Xiang: Tianjin Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The yeast protein Rad5 and its orthologs in other eukaryotes promote replication stress tolerance and cell survival using their multiple activities, including ubiquitin ligase, replication fork remodeling and DNA lesion targeting activities. Here, we present the crystal structure of a nearly full-length Rad5 protein. The structure shows three distinct, but well-connected, domains required for Rad5’s activities. The spatial arrangement of these domains suggest that different domains can have autonomous activities but also undergo intrinsic coordination. Moreover, our structural, biochemical and cellular studies demonstrate that Rad5’s HIRAN domain mediates interactions with the DNA metabolism maestro factor PCNA and contributes to its poly-ubiquitination, binds to DNA and contributes to the Rad5-catalyzed replication fork regression, defining a new type of HIRAN domains with multiple activities. Our work provides a framework to understand how Rad5 integrates its various activities in replication stress tolerance.

Date: 2021
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DOI: 10.1038/s41467-020-20538-w

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