MTBP (MDM2 binding protein) is a critical replication initiation factor that regulates DNA replication timing and origin selection in human cells. MTBP functions as part of the TRESLIN-MTBP complex, which is essential for origin firing and the maturation of pre-replicative complexes into replisomes 1. The protein acts as a key limiting factor for replication initiation, with its loading onto phosphorylated MCM2-7 double hexamers controlled by opposing phosphorylation events that ultimately determine initiation zones and establish replication timing 2. MTBP binds chr8 in a cell cycle-dependent manner, requiring TRESLIN for proper association during G1 phase but functioning independently during S phase 3. Beyond replication control, MTBP serves as a transcriptional cofactor for the oncogene c-MYC, promoting MYC-mediated transcriptional activity, proliferation, and cellular transformation 4. Depletion of MTBP increases replication fork speed above tolerated thresholds, leading to DNA damage and replication stress 5. In cancer contexts, MTBP shows predominantly oncogenic properties with overexpression correlating with adverse prognoses across multiple cancer types, though its role may vary by cancer type 6. The selective interaction between MTBP-TRESLIN and phosphorylated RecQL4 helps differentiate between baseline and dormant replication origins 7.