CDT1 overexpression suppresses DNA replication and induces DNA damage, suggesting a mechanism for cancer development

A research group led by Drs. Shusuke Tada and Takashi Tsuyama at the Department of Molecular Biology, Faculty of Pharmaceutical Sciences, Toho University, has demonstrated that overexpression of Cdc10-dependent transcript 1 (CDT1), a key regulator of DNA replication initiation, induces DNA damage and potentially results in genetic mutations. Although previous studies have linked CDT1 overexpression to cellular transformation and tumorigenesis, the underlying mechanism has remained unclear. The findings not only reveal the impact of CDT1 overexpression on DNA replication progression post initiation but also provide molecular insights into its role in cancer development. This research was published online in the journal FEBS Open Bio on September 26, 2025.

During the initiation of DNA replication, the mini-chromosome maintenance (MCM) complex, a DNA helicase, binds to replication origins and promotes replication fork progression. The replication fork may stall due to various factors, and prolonged stalling may cause DNA breaks, resulting in cell death or cancer. Although CDT1 plays an essential role in loading the MCM complex onto replication origins, its overexpression has been implicated in oncogenesis. However, the underlying mechanism remains unclear. By analyzing various CDT1 mutants and establishing cell lines with inducible CDT1 overexpression, the research group demonstrated that CDT1 overexpression suppresses replication fork progression and induces DNA damage. These findings reveal a novel function of CDT1 in DNA replication and provide molecular insights into the oncogenic process triggered by its overexpression.

Key Findings:

• In cultured human cells, CDT1 overexpression suppresses the progression of DNA replication.
• This suppression depends on the interaction between CDT1 and the mini-chromosome maintenance (MCM) complex, a DNA helicase.
• CDT1 overexpression induces DNA damage.
• These findings advance the molecular understanding of cancer development driven by CDT1 overexpression.

Journal:
FEBS Open Bio (Online publication: September 26, 2025)

Article Title:
Overexpression of CDT1 inhibits cell cycle progression at S phase by interacting with the mini-chromosome maintenance complex and causes DNA damage

Authors:
Takashi Tsuyama, Nonoka Takayama, Rina Tanaka, Yuuki Arai, Yohko Yamaguchi, Yuko Nawata, Yutaro Azuma, Shusuke Tada*

DOI:
10.1002/2211-5463.70127