cdc18 (Cdc6/Cdc18) — S. pombe — Review notes

UniProt: P41411 (CDC18_SCHPO), 577 AA. PomBase SPBC14C8.07c. Member of CDC6/cdc18 family (AAA+ ATPase).
Human/budding-yeast ortholog: Cdc6 / CDC6.

Core biology

Cdc18 is the fission-yeast ortholog of Cdc6, an AAA+ ATPase pre-replicative complex (pre-RC)
component essential for DNA replication licensing. It is recruited to ORC-bound origins and, with
Cdt1, loads the MCM2-7 replicative helicase onto origins, licensing them for a single round of
firing. Cdc18 is the rate-limiting S-phase initiator; its abundance is tightly cell-cycle-controlled
at the level of transcription (MBF/Cdc10 at START) and proteolysis (CDK phosphorylation → SCF^Pop1/Pop2
ubiquitination → 26S proteasome). Overexpression drives re-replication. Cdc18 also contributes to the
S-phase/replication checkpoint by anchoring Rad3-Rad26 to chromatin at stalled forks.

Key evidence

• Essential for DNA replication; couples S phase to START and mitosis; overexpression drives repeated
  rounds of DNA synthesis without mitosis; protein periodic, peaks at G1/S; nuclear localization.
  PMID:8521469
  PMID:8521469
  PMID:8521469
  PMID:8521469

• MCM loading / pre-RC: chromatin binding of mcm4 requires orc1 and cdc18 (= Cdc6 ortholog); occurs at
  anaphase B; mcm4 release during S phase requires replication; cdc18 overexpression drives re-replication
  with mcm4 chromatin-bound.
  PMID:10747035
  PMID:10747035
  PMID:10747035

• Degradation by SCF^Pop1: pop1 binds Cdc18 in vivo; pop1 mutant accumulates Cdc18 (ubiquitinated forms);
  controls genome ploidy.
  PMID:9203581
  PMID:9203581
  PMID:9203581

• Degradation by Sud1/Pop2: sud1+ binds Cdc18 in a phosphorylation-dependent manner; prevents re-replication.
  PMID:9653157
  PMID:9653157
  PMID:9653157

• Pop1/Pop2 form SCF complex that binds and directs proteolysis of Cdc18; Cdc18 binding to Pop2 depends on Pop1.
  PMID:10209119
  PMID:10209119

• SCF^Pop1/Pop2 also degrades S-phase cyclin Cig2 (this is the substrate in PMID:14970237; Cdc18 is a
  known substrate of the same ligase but the Cdc18-Pop1 IPI is annotated to this paper as physical interaction).
  PMID:14970237

• Re-replication control via redundant CDK phosphorylation of Cdc18 and Orp2/Orc2; deregulated (overexpressed,
  phospho-site mutant) Cdc18 drives re-replication.
  PMID:11486016
  PMID:11486016

• S-phase checkpoint maintenance: at stalled forks Cdc18 persists in a chromatin-bound complex with Rad3-Rad26;
  Rad26 directly binds Cdc18; Cdc18 anchors Rad3-Rad26 to chromatin (basis for GO:0140463 chromatin-protein
  adaptor activity IPI with rad3 SPAC9E9.08 and rad26 SPBC216.05; GO:0000785 chromatin IDA; GO:0033314 checkpoint).
  PMID:17531813
  PMID:17531813
  PMID:17531813

• Meiosis: Cdc18 protein synthesis is down-regulated during meiosis; lack of cdc18 prevents DNA replication
  in spores (nuclear localization assayed in S. pombe).
  PMID:15278909

GO annotation review reasoning

• GO:0005634 nucleus (IBA + IDA PMID:15278909): ACCEPT. Nuclear localization is well supported.
• GO:0006270 DNA replication initiation (IBA + IEA): ACCEPT (IBA core), the IEA is redundant — keep.
• GO:0003688 DNA replication origin binding (IBA): Cdc18 is recruited to origins via ORC; ACCEPT (origin-associated).
• GO:0033314 mitotic DNA replication checkpoint signaling (IBA): ACCEPT, supported by PMID:17531813 (checkpoint maintenance).
• GO:0005524 ATP binding (IEA/ISM): ACCEPT — AAA+ ATPase, Walker A P-loop FT BINDING 199..206.
• GO:0016887 ATP hydrolysis activity (IEA): ACCEPT (AAA+ ATPase); ATPase activity is core to Cdc6 family.
• GO:0006325 chromatin organization (IEA, from GO:0140463 link): over-broad; the real function is checkpoint
  anchoring, not chromatin organization. MARK_AS_OVER_ANNOTATED.
• GO:0051301 cell division (IEA keyword/InterPro): generic; KEEP_AS_NON_CORE.
• GO:0005515 protein binding (IPI x4): bare protein binding, uninformative. The interactors are pop1, pop2
  (degradation) and via 14970237. Replace with more informative terms / mark over-annotated; recommend MODIFY
  to ubiquitin-dependent context is not an MF; best practice: NON_CORE or note. Use MARK_AS_OVER_ANNOTATED with
  note to prefer adaptor/specific terms (the informative MF GO:0140463 already captured separately).
• GO:1902975 mitotic DNA replication initiation (IMP PMID:8521469): ACCEPT — core.
• GO:0140463 chromatin-protein adaptor activity (IPI PMID:17531813, with rad3/rad26): ACCEPT — informative MF
  for anchoring Rad3-Rad26 to chromatin.
• GO:0140530 MCM complex loading (IMP PMID:10747035, PMID:11532929): ACCEPT — core helicase-loading function.
• GO:0000785 chromatin (IDA PMID:17531813): ACCEPT — chromatin-bound at stalled forks/origins.
• GO:0005656 nuclear pre-replicative complex (ISO): ACCEPT — Cdc18 is a pre-RC component.
• GO:0043596 nuclear replication fork (IC from pre-RC): plausible but indirect; KEEP_AS_NON_CORE.
• GO:1902985 mitotic pre-replicative complex assembly (ISO): ACCEPT — core.

PMID:11532929 not in cache; title (PomBase): MCM complex loading paper. Defer/ACCEPT per PomBase IMP.