The human origin recognition complex (ORC) is essential for pre-RC assembly, mitosis and maintenance of nuclear structure

The origin recognition complex (ORC) cooperates with CDC6, MCM2-7, and
CDT1 to form pre-RC complexes at origins of DNA replication. Here, using
tiling-sgRNA CRISPR screens, we report that each subunit of ORC and CDC6
is essential in human cells. Using an auxin-inducible degradation system,
we created stable cell lines capable of ablating ORC2 rapidly, revealing
multiple cell division cycle phenotypes. The primary defects in the
absence of ORC2 were cells encountering difficulty in initiating DNA
replication or progressing through the cell division cycle due to reduced
MCM2-7 loading onto chromatin in G1 phase. The nuclei of ORC2-deficient
cells were also large, with decompacted heterochromatin. Some
ORC2-deficient cells that completed DNA replication entered into, but
never exited mitosis. ORC1 knockout cells also demonstrated extremely slow
cell proliferation and abnormal cell and nuclear morphology. Thus, ORC
proteins and CDC6 are indispensable for normal cellular proliferation and
contribute to nuclear organization.