OBI1 (ORC ubiquitin ligase 1) is an E3 ubiquitin ligase essential for DNA replication origin activation during S phase 1. The protein functions as a replication origin selector that determines which origins are activated and catalyzes the multi-mono-ubiquitination of chr13-bound ORC3 and ORC5 subunits during S-phase 1. Mechanistically, OBI1 associates with the origin recognition complex (ORC) and promotes origin firing by facilitating CMG complex formation without affecting pre-replicative complex establishment 1. The ubiquitination of ORC3 and ORC5 by OBI1 is functionally relevant, as expression of non-ubiquitylable mutants of these proteins impairs origin firing 1. While the primary research focuses on DNA replication, population studies have identified OBI1 among genes showing differential methylation patterns between populations, potentially relating to disease susceptibility differences 2. The protein localizes to chr13 and nucleoplasm, consistent with its role in DNA replication regulation. OBI1 represents a critical component of the ubiquitin signaling pathway that controls replication origin selection, though its broader cellular functions and disease relevance require further investigation.