module: dmel_replication_origin_licensing_activation
title: Replication origin licensing and activation in Drosophila melanogaster
label: Origin licensing and activation
module_type: BIOLOGICAL_PROCESS
description: >-
  Eukaryotic DNA replication starts in two steps that are separated in the cell
  cycle. In G1, the origin recognition complex (ORC) binds replication origins
  and, with Cdc6 and Cdt1 (Double parked in Drosophila), loads the MCM2-7
  helicase core as an inactive double hexamer around double-stranded DNA; this
  is origin licensing. In S phase, the Dbf4-dependent kinase (Cdc7 with its
  regulatory subunit Chiffon) and cyclin-dependent kinases trigger the
  recruitment of Cdc45 and the four-subunit GINS complex onto MCM2-7, forming
  the active CMG (Cdc45-MCM-GINS) helicase that unwinds DNA at the replication
  fork. Restricting licensing to G1 and activation to S phase ensures that each
  origin fires only once per cell cycle.
summary: >-
  ORC-dependent loading of the MCM2-7 helicase onto origins and its
  DDK-triggered conversion into the active CMG helicase.
concepts:
  - {id: GO:0006270, label: DNA replication initiation}
cellular_components:
  - {id: GO:0005634, label: nucleus}
parts:
  - id: orc
    label: Origin recognition complex
    role: origin recognition
    description: Six-subunit complex that binds replication origins and recruits the licensing machinery.
    group: ORC
    complex: true
    complex_term: {id: GO:0000808, label: origin recognition complex}
    processes:
      - {id: GO:0036388, label: pre-replicative complex assembly}
  - id: mcm_loading_factors
    label: MCM2-7 loading factors Cdc6 and Cdt1
    role: helicase loading
    description: >-
      Cdc6 and Cdt1 (Double parked) cooperate with ORC to load MCM2-7 onto
      origin DNA. They are not members of the FlyBase groups and are added as
      textbook licensing factors.
    genes: [Cdc6, dup]
    complex: false
    processes:
      - {id: GO:0036388, label: pre-replicative complex assembly}
  - id: mcm2_7
    label: MCM2-7 helicase core
    role: licensed helicase core
    description: >-
      Heterohexameric AAA+ helicase motor (Mcm2, Mcm3, Mcm4/Dpa, Mcm5, Mcm6,
      Mcm7) loaded as an inactive double hexamer at licensed origins.
    group: MCM2-7
    complex: true
    complex_term: {id: GO:0042555, label: MCM complex}
  - id: ddk
    label: Dbf4-dependent kinase
    role: helicase activation kinase
    description: >-
      Cdc7 kinase with its Dbf4-family regulatory subunit Chiffon; DDK
      phosphorylates loaded MCM2-7 to promote CMG assembly.
    group: DDK
    complex: true
    complex_term: {id: GO:0031431, label: Dbf4-dependent protein kinase complex}
    unit_functions:
      Cdc7: {id: GO:0004674, label: protein serine/threonine kinase activity}
  - id: cmg
    label: CMG helicase
    role: active replicative helicase
    description: >-
      Active helicase formed when Cdc45 and GINS (Psf1, Psf2, Psf3, Sld5) join
      MCM2-7. GINS is a stable four-subunit subcomplex of CMG.
    group: CMG
    complex: true
    complex_term: {id: GO:0071162, label: CMG complex}
    function: {id: GO:0003678, label: DNA helicase activity}
    processes:
      - {id: GO:0006270, label: DNA replication initiation}
connections:
  - {source: orc, target: mcm2_7, connection_type: PRECEDES, description: ORC bound at origins recruits and loads MCM2-7.}
  - {source: mcm_loading_factors, target: mcm2_7, connection_type: POSITIVELY_REGULATES, description: Cdc6 and Cdt1 are required for MCM2-7 loading.}
  - {source: mcm2_7, target: cmg, connection_type: PRECEDES, description: Loaded MCM2-7 double hexamers are converted into CMG helicases in S phase.}
  - {source: ddk, target: cmg, connection_type: POSITIVELY_REGULATES, description: DDK phosphorylation of MCM2-7 promotes Cdc45 and GINS recruitment.}
notes: >-
  Boundary. The module covers origin recognition, MCM2-7 loading and helicase
  activation. The FlyBase groups CMG, GINS and MCM2-7 overlap; MCM2-7 subunits
  appear both in the loaded MCM2-7 part and in the CMG part, and GINS is
  represented inside the CMG part rather than as a separate part. Cdc6 and dup
  (Cdt1) are not FlyBase members of these groups and were added as textbook
  licensing factors. Other firing factors (for example Mcm10, Treslin/Sld3 and
  TopBP1/Dpb11 homologs) and the replicative polymerases (see
  dmel_dna_polymerase_complexes) are outside the module.