cdc7 (SPBC21.06c, P41892) — S. pombe SIN initiating kinase — review notes

CRITICAL identity caveat

S. pombe cdc7 is the SIN (Septation Initiation Network) protein kinase, NOT the
DDK/Dbf4-dependent replication kinase. The replication initiation kinase in fission yeast
(the true Cdc7/CDC7 ortholog of budding yeast Cdc7 and human CDC7) is Hsk1. Therefore
no DNA-replication / origin-firing / DDK function should be imported onto pombe cdc7.

Core function

Cdc7 is the most upstream protein Ser/Thr kinase of the SIN. It is recruited to the
spindle pole body (SPB) by GTP-bound Spg1 (on the Cdc11–Sid4 scaffold), and acts at the
top of the SIN kinase cascade (Cdc7 -> Sid1–Cdc14 -> Sid2–Mob1) to trigger contractile-ring
constriction and septum formation (cytokinesis). It localizes asymmetrically to one SPB
(the new/daughter SPB) in late anaphase, which is important for SIN regulation.

Key evidence

• Cdc7 is a protein kinase essential for cell division; loss prevents septum formation and
  cytokinesis; overexpression drives multiple rounds of septation; multi-septation requires
  kinase activity and depends on cdc11.
  PMID:8039497
  PMID:8039497
  PMID:8039497
  Note: DNA synthesis and mitosis are explicitly UNAFFECTED in cdc7 loss — confirms this is NOT a replication kinase.

• Cdc7 interacts with the Spg1 GTPase; Spg1 activity is needed for Cdc7 SPB localization
  (not for its in vitro kinase activity). Cdc7 is on both SPBs early in mitosis then on only
  one pole during anaphase B (asymmetric segregation).
  PMID:9420333
  PMID:9420333

• Spg1-GTP binds Cdc7 and recruits it to SPB; SPB-localized Cdc7 promotes activation of
  Sid2 kinase, which moves to the division site to trigger cytokinesis.
  PMID:19736319
  Cdc7 fluorescence at single SPB increases ~2.5-fold in late anaphase (Etd1/Spg1 hyperactivation reporter).
  PMID:19736319

• Cdc7 kinase activity is required for mitotic hyperphosphorylation of the SIN scaffold
  Cdc11; cdc11 is a Cdc7 substrate/target in vivo.
  PMID:12546793
  Supports both protein Ser/Thr kinase activity (EXP) and septation initiation signaling.

• Cdc11 + Sid4 form the SPB scaffold that anchors all SIN proteins (including Cdc7) at SPB.
  PMID:11676915

• Asymmetric Spg1/Cdc7 segregation: Byr4–Cdc16 GAP localizes to the SPB lacking Cdc7; in
  byr4- mutants Cdc7 localizes symmetrically.
  PMID:10381387
  PMID:10799520

• SIP/PP2A (Csc1) complex dephosphorylates Cdc11 and propagates SIN asymmetry; Cdc7 and
  Sid1 localize asymmetrically to the newly duplicated SPB in late anaphase.
  PMID:22119525

• SIN (including Cdc7) is required for spore formation in meiosis; Cdc7 and Sid1 associate
  with the meiotic SPB in meiosis II when forespore membrane deposition begins.
  PMID:16787941
  Supports meiotic SPB localization (GO:0035974).

• Dma1-dependent degradation of Cdc7 (and Cdc11, Sid4) after meiosis II; Cdc7 localization to
  meiotic SPB; in meiosis GTP-Spg1 is not the main determinant of Cdc7 SPB timing.
  PMID:24838944
  Supports meiotic SPB localization (GO:0035974).

• Etd1 links SIN to cytokinesis; Cdc7-GFP at SPB used as readout of Spg1 activity.
  PMID:15933715
  Supports old/new mitotic SPB localization.

• SIN activity (Cdc7-GFP at SPB used as marker) disperses Cdr2/Mid1 type-1 nodes.
  PMID:25501814
  Supports mitotic SPB localization (IDA via Cdc7-GFP marker).

• Pcp1 / Pmo25 papers use Cdc7-GFP as the established asymmetric daughter-SPB marker.
  PMID:19942852
  PMID:16325501
  These support new mitotic SPB (GO:0071958) localization of Cdc7 (IDA, Cdc7-GFP imaged directly).

UniProt notes

• EC 2.7.11.1 (non-specific Ser/Thr kinase). Protein kinase domain 9-259, ATP binding 15-23, 38;
  Mg2+ cofactor; active site 131.
• SUBUNIT: Interacts with spg1; seems to interact with cdc11 [PMID:9203579 — INTERACTION WITH SPG1; not cached].
• Family: protein kinase superfamily, Ser/Thr protein kinase family, CDC7 subfamily.

Annotation-by-annotation judgments

• MF kinase activities (GO:0004674 serine/threonine, GO:0106310 serine, GO:0004672 protein kinase,
  GO:0005524 ATP binding): all ACCEPT. EXP/IMP evidence for Ser/Thr kinase activity is direct (8039497,
  9420333, 12546793). IEA from RHEA/InterPro/EC consistent. ATP binding consistent with kinase domain.
• GO:0000165 MAPK cascade (IBA): scrutinize. pombe cdc7 is a SIN kinase cascade kinase, NOT a MAPK
  cascade component. MAPK cascade is a defined three-tiered MAP3K->MAP2K->MAPK module; SIN is a distinct
  GTPase-regulated kinase cascade. IBA from PANTHER groups cdc7 with budding yeast CDC15 (MEN kinase) /
  STE20-like kinases. This IBA over-propagates "MAPK cascade" onto a non-MAPK kinase. Mark as
  MARK_AS_OVER_ANNOTATED / NOT a core MAPK function. No experimental support for cdc7 in a MAPK cascade.
  Better: septation initiation signaling (already separately annotated). Action: REMOVE (over-propagated
  IBA, no evidence cdc7 acts in a MAPK cascade in pombe).
• Septation initiation signaling GO:0031028 (EXP x2, IMP): ACCEPT — core.
• GO:0140281 positive regulation of mitotic division septum assembly (IMP, 8039497): ACCEPT — core.
• SPB CC terms (GO:0044732 mitotic SPB; GO:0071957 old mitotic SPB; GO:0071958 new mitotic SPB;
  GO:0035974 meiotic SPB): all ACCEPT, direct IDA via Cdc7 antibody/Cdc7-GFP imaging. Asymmetry to
  new/daughter SPB is well established.