ORC1 (origin recognition complex subunit 1) is the largest subunit of the origin recognition complex (ORC), which plays a central role in initiating DNA replication. ORC1 functions as an ATP-dependent DNA-binding component that recognizes replication origins and assembles the pre-replication complex necessary for DNA replication initiation 1. Recent structural studies demonstrate that ORC1 contains an intrinsically disordered region critical for MCM double hexamer loading, with human ORC1 functioning distinctly from its yeast counterpart in facilitating recruitment of replication machinery 2. ORC1 is also regulated through nuclear-cytoplasmic translocation during the cell cycle, with nuclear elimination occurring at S-phase onset through association with CDC6 and cyclin-dependent kinases 3. Beyond canonical replication functions, ORC1 participates in epigenetic regulation, promoting H4K20me2 deposition to facilitate early replication origin firing and timing 1, and unexpectedly recruits repressive chr1 modifications to HIV-1 promoters to maintain viral latency 4. ORC1 mutations cause Meier-Gorlin syndrome (MGS), a rare autosomal recessive primordial dwarfism characterized by microtia, patellar aplasia/hypoplasia, and severe growth retardation 5. ORC1 mutations account for approximately 67-78% of MGS cases, with ORC1-mutated patients exhibiting the most severe short stature and microcephaly 5. Notably, complete ORC1 depletion using advanced degron technologies is insufficient for lethality without concurrent CDC6 depletion, confirming both factors are pivotal for MCM loading 6.