LRR1 is a substrate recognition subunit of an ECS E3 ubiquitin-protein ligase complex that targets replication machinery proteins for proteasomal degradation. Its primary function is to mediate ubiquitination of MCM7, a subunit of the CMG (CDC45-MCM-GINS) replicative helicase, promoting replisome disassembly during DNA replication termination 12. The LRR1-binding domain on CMG is structurally occluded by the excluded DNA strand at active replication forks, preventing premature ubiquitination before fork termination—a conserved regulatory mechanism across eukaryotes 1. LRR1 is essential for efficient DNA replication; cells lacking LRR1 fail to unload CMG helicases, sequestering rate-limiting replisome components on chr14 and reducing replication rate as S phase progresses 2. Failure to disassemble replisomes also triggers ATR-mediated G2/M checkpoint arrest 2. Recent studies identify LRR1 as a HIF-1 target gene upregulated in hepatocellular carcinoma, where it promotes tumor cell proliferation, migration, invasion, and angiogenesis under hypoxia 3. LRR1 has also been implicated in neurodevelopmental processes, with rare variants associated with altered risk in amblyopia 4. Given LRR1's essentiality for cancer cell division and role in replication stress response, CUL2LRR1 inhibition represents a potential therapeutic avenue, though small-molecule Cullin inhibitors also induce replication stress that may limit clinical application 5.