cds1 (S. pombe) — gene review notes

UniProt: Q09170 (RAD53_SCHPO). Gene: cds1 / SPCC18B5.11c. 460 aa Ser/Thr kinase, EC 2.7.11.1.
Ortholog of human CHK2 and budding-yeast Rad53 (CHEK2 subfamily). Domain architecture:
N-terminal FHA domain (res ~60-116) + C-terminal protein kinase domain (res ~167-433);
SQ/TQ regulatory motif near the N-terminus (T11Q12). Active-site proton acceptor Asp294.

Core identity / function

Cds1 is the effector Ser/Thr protein kinase of the DNA replication (intra-S) checkpoint
in fission yeast. It is the major effector of the replication checkpoint, activated
specifically in S phase when replication forks stall (e.g. hydroxyurea/HU, nucleotide
depletion, or replication encountering DNA damage). It is distinct from Chk1, the G2 DNA-damage
checkpoint effector kinase.

• Original discovery as a multicopy suppressor of a DNA pol-alpha ts mutant; "checking DNA synthesis";
  blocks mitosis in S phase: PMID:7723827
• Cds1 enforces the S-M checkpoint coupling mitosis to completion of S phase, and controls
  replicational stress tolerance: PMID:11313465
• Major effector of replication checkpoint: PMID:16618806
• Ortholog of Chk2: PMID:19357077

Activation mechanism (MF = protein Ser/Thr kinase; activation regulation)

Two-stage activation: priming by Rad3(ATR) via mediator Mrc1, then FHA-dependent dimerization
and autophosphorylation.
- T11 phosphorylated by Rad3/ATM required for activation: PMID:11313465
- Mrc1 recruits Cds1 via FHA-phospho-Mrc1, then dimerization/autophosphorylation: PMID:16618806
- Autoactivation requires autophosphorylation of activation-loop Thr328; C-terminal tail autoinhibits: PMID:19357077
- Interacts with Rad26 (Rad3 partner); autophosphorylated (UniProt; PMID:9450932, PMID:18257517).

Direct substrates / downstream targets

• Cdc25 phosphatase — Cds1 (or Chk1) phosphorylates Cdc25 on S99/S192/S359, creating 14-3-3 binding sites, keeping Cdc2 inhibited: PMID:9774107
• Hsk1 (Cdc7 ortholog) — Cds1-dependent phosphorylation in vivo and direct substrate in vitro: PMID:11027263
• Dna2 — Cds1 phosphorylates Dna2-S220 to prevent stalled fork reversal: PMID:22682245
• Nrm1 (MBF repressor) — Cds1 phosphorylates Nrm1, relieving MBF repression to drive G1-S transcription of replication/repair genes: PMID:18682565 (This is the PMID:18682565 IPI "protein binding" annotation partner = Nrm1/O42913; also the IntAct nrm1 interaction.)
• Mcm4 — binds Cds1 and is Cds1-dependently phosphorylated upon checkpoint activation: PMID:18180284 (PMID:18180284 IPI partner SPCC16A11.17 = mcm4/cdc21.)
• Rgf1 (Rho1 GEF) — Cds1- and Rad24-dependent nuclear accumulation under chronic replication stress: PMID:24478458
• Downstream Mus81 / Rqh1 / Rhp51 pathway for S-phase damage slowing: PMID:19037101
• UniProt also lists Rad60 as a Cds1 phosphorylation target (PMID:12897162).

Biological processes

• Mitotic DNA replication checkpoint signaling (GO:0033314): PMID:11313465 (S-M checkpoint).
• Mitotic intra-S DNA damage checkpoint signaling (GO:0031573): replication slowing on damage:
  PMID:19037101
  PMID:12032307
  Original IGI (with hus1/SPAC3H5.06c) blocking mitosis in S: PMID:7723827.
• Meiotic G2/MI DNA replication checkpoint signaling (GO:0033315): Cds1 absolutely required, plays a more prominent role than in mitosis: PMID:10521402
  Downstream Mei4 regulation of nuclear movements: PMID:25492408
• Fork stabilization / protection — preventing fork reversal via Dna2: PMID:22682245. NOTE: the
  precise GO term "replication fork protection" (GO:0048478) is OBSOLETE; GO:0031297 (replication
  fork processing) is the recommended live term.

Localization

• IDA nucleus: [PMID:24478943 - Cds1 chromatin recruitment/activity, nuclear]. Also HDA global
  localization (nucleus, cytosol, cell division site) from ORFeome study PMID:16823372 - large-scale
  GFP localization, lower confidence for site-of-action.
• IBA nucleus + cytoplasm from GO_Central.

NOT in GOA review list but in UniProt DR

• GO:0051598 meiotic recombination checkpoint signaling (IBA) — present in uniprot but not in goa.tsv list.
• Mek1 (PMID:21084840) is a Cds1/Rad53-related kinase that is itself studied; the PomBase IDA assigns
  protein Ser/Thr kinase activity to cds1 from this paper's context — kinase activity is well-supported regardless.

Curation conclusions

• Core MF: protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524).
• Core BP: mitotic DNA replication checkpoint signaling (GO:0033314), mitotic intra-S DNA damage
  checkpoint signaling (GO:0031573); meiotic counterpart GO:0033315 (core in meiosis).
• "protein binding" (GO:0005515) IPI annotations are uninformative per curation guidance; partners are
  substrates (Nrm1, Mcm4) so MARK_AS_OVER_ANNOTATED / not core.
• "mitotic DNA damage checkpoint signaling" (GO:0044773, IBA) is imprecise for Cds1, whose role is the
  intra-S / replication checkpoint, not the G2 DNA-damage checkpoint (that is Chk1). MODIFY to intra-S.
• HDA cytosol / cell division site likely reflect bulk localization, not site of action — non-core.