NSMF Mitigates Excessive Replication Stress to Facilitate Colorectal Cancer Progression

Replication stress is a fundamental driver of genomic instability and tumorigenesis, but excessive levels result in irreparable DNA damage, requiring precise regulation to support cancer cell proliferation and survival. Here, we identify NSMF as a critical regulator of replication stress in colorectal cancer (CRC), enabling cancer cells to prevent catastrophic DNA damage while sustaining proliferation. NSMF expression is elevated in CRC and correlates with replication stress level. In ApcMin/+ mice, NSMF knockout selectively induced replication-dependent DNA damage in tumors, suppressing tumor growth and prolonging survival without harming normal tissues. Mechanistically, NSMF deficiency impairs replication fork progression under stress, triggering DNA damage, growth arrest, and senescence. Moreover, NSMF overexpression conferred tolerance to oncogene-induced replication stress, allowing normal cells to evade senescence. These findings establish NSMF as a crucial safeguard against lethal replication stress, highlighting its potential as a therapeutic target for CRC suppression.