DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation

Xiaohua Xu, Chou-Wei Chang, Min Li, Kenneth Omabe, Nhung Le, Yi-Hsuan Chen, Feng Liang and Yilun Liu ()
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Xiaohua Xu: Thermo Fisher Scientific
Chou-Wei Chang: Vesigen Therapeutics
Min Li: City of Hope
Kenneth Omabe: City of Hope
Nhung Le: City of Hope
Yi-Hsuan Chen: University of Southern California
Feng Liang: University of Southern California
Yilun Liu: City of Hope

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Deletion of the conserved C-terminus of the Rothmund-Thomson syndrome helicase RECQ4 is highly tumorigenic. However, while the RECQ4 N-terminus is known to facilitate DNA replication initiation, the function of its C-terminus remains unclear. Using an unbiased proteomic approach, we identify an interaction between the RECQ4 N-terminus and the anaphase-promoting complex/cyclosome (APC/C) on human chromatin. We further show that this interaction stabilizes APC/C co-activator CDH1 and enhances APC/C-dependent degradation of the replication inhibitor Geminin, allowing replication factors to accumulate on chromatin. In contrast, the function is blocked by the RECQ4 C-terminus, which binds to protein inhibitors of APC/C. A cancer-prone, C-terminal-deleted RECQ4 mutation increases origin firing frequency, accelerates G1/S transition, and supports abnormally high DNA content. Our study reveals a role of the human RECQ4 C-terminus in antagonizing its N-terminus, thereby suppressing replication initiation, and this suppression is impaired by oncogenic mutations.

Date: 2023
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DOI: 10.1038/s41467-023-36968-1

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