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

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 G(1)/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. RECQ4 mutations contribute to multiple developmental diseases and tumorigenesis. Here the authors describe how a highly oncogenic RECQ4 mutation alters the control of DNA synthesis, leading to abnormal DNA content and cell growth.

Automated summary

Deletion of the conserved C-terminus of the Rothmund-Thomson syndrome helicase RECQ4 leads to highly tumorigenic effects. An interaction between the RECQ4 N-terminus and the anaphase-promoting complex/cyclosome (APC/C) is identified, which enhances DNA replication and inhibits replication inhibitors. However, the RECQ4 C-terminus blocks this function by binding to protein inhibitors of APC/C. Cancer-prone RECQ4 mutations accelerate DNA synthesis and contribute to multiple developmental diseases and tumorigenesis.