Choi Younghee, Park Seowoo, Yang Seojin, Kim Eunju, Cho Youngwon, Yang Hye-Ju, Yi Eugene C, Song Sang-Hyun, Kim Tae-You
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea.
Cancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
Sci Rep. 2025 Oct 16;15(1):36122. doi: 10.1038/s41598-025-21082-7.
Colorectal cancer (CRC) is a leading cause of cancer-related mortality, necessitating the development of novel therapeutic strategies. In the present study, we identified TP53-regulating kinase (TP53RK) as a critical regulator of CRC cell survival and proliferation using a custom clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 library screen targeting serine/threonine kinase-related genes. TP53RK was significantly overexpressed in CRC tissues and was correlated with copy number amplification. Functional validation revealed that TP53RK depletion induced DNA replication stress, apoptosis, and cell cycle arrest, independent from p53 status. Mechanistically, TP53RK stabilized cell division cycle 7 (CDC7), a key kinase regulating DNA replication origin activation, ensuring robust minichromosome maintenance complex protein (MCM) phosphorylation and replication fork progression. Disruption of the TP53RK-CDC7 axis led to reduced MCM2 enrichment at replication origins and impaired DNA replication dynamics. Moreover, TP53RK overexpression sensitized cells to DNA replication stress (aphidicolin) and CDC7 inhibition (XL413), highlighting its potential as a therapeutic strategy. These findings establish TP53RK as a pivotal regulator of DNA replication fidelity and genomic stability, thereby providing a promising therapeutic target for CRC.
