{"entity":{"id":"dna-replication-licensing","kind":"pathway","name":"DNA replication & origin licensing","aka":[],"tldr":"Before a cell divides it must copy three billion letters of DNA exactly once, 'licensing' thousands of start points in advance and firing them in waves. Cancers driven by MYC, cyclin E or RAS fire excess start points too fast, and antimetabolites such as 5-FU, topoisomerase poisons such as irinotecan and platinum drugs all jam this copying machinery.","summary":"In G1, ORC binds origins and with CDC6 and CDT1 loads double MCM2-7 hexamers (licensing). At S-phase entry CDK2 and DDK (CDC7) convert MCM into the active CMG helicase (with CDC45, GINS), recruiting polymerases: Pol α-primase starts, Pol ε (leading) and Pol δ (lagging) extend, with PCNA as clamp, RPA coating single strands, and Okazaki fragments joined by FEN1/LIG1. Re-licensing within one cycle is prevented by CDT1 degradation (CRL4-CDT2), geminin, and CDK activity. Oncogenes (MYC, cyclin E, RAS) shorten G1, fire excess and ectopic origins, and cause origin-fork collisions and dNTP exhaustion, the root of replication stress. Chemotherapy exploits this: antimetabolites deplete dNTPs (5-FU, methotrexate, pemetrexed, hydroxyurea inhibits RNR) or terminate chains (gemcitabine, cytarabine); topoisomerase I poisons (irinotecan, topotecan, ADC payloads SN-38, DXd, exatecan) trap the enzyme ahead of the fork; platinum crosslinks block polymerases. POLQ, POLA1 and CDC7 inhibitors are experimental.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Eukaryotic_DNA_replication","links":[{"label":"Bell & Dutta, DNA replication in eukaryotic cells (Annu Rev Biochem 2002)","url":"https://doi.org/10.1146/annurev.biochem.71.110601.135425"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","topoisomerase-inhibitors","platinum","adc"],"targets":["kras","cdk4-6","atr","trop2","her2"],"drugs":["gemcitabine","fluorouracil","methotrexate","pemetrexed","hydroxyurea","irinotecan","topotecan","trastuzumab-deruxtecan","sacituzumab-govitecan"],"companies":[],"institutions":[],"pathways":["replication-stress","cell-cycle-engine-cdks","ddr","myc"],"terms":["topoisomerase-i-payloads","sn-38","dxd","exatecan","payload"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bell-annu-rev-biochem"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Printing a 3,000-page book on thousands of small presses at once. Licensing hands out one ticket per press before printing begins; firing starts them in waves. Cancer starts far too many presses with too little ink (nucleotides), so pages smear and tear, and many chemotherapies simply cut off the ink supply or jam the rollers.","nodes":[{"id":"orc","label":"ORC, CDC6, CDT1","x":12,"y":15},{"id":"mcm","label":"MCM2-7 loaded (licence)","x":40,"y":15},{"id":"gem","label":"Geminin, CRL4-CDT2","x":40,"y":45},{"id":"cdk","label":"CDK2 / DDK firing","x":68,"y":15,"targetId":"cdk4-6"},{"id":"cmg","label":"CMG helicase + Pol ε/δ","x":68,"y":45},{"id":"dntp","label":"dNTP supply (RNR)","x":90,"y":75},{"id":"fork","label":"Replication fork","x":68,"y":75},{"id":"top1","label":"TOP1 (chemo, ADC payloads)","x":40,"y":75,"targetId":"trop2"},{"id":"onc","label":"MYC, cyclin E: excess origins","x":12,"y":45,"targetId":"kras"},{"id":"stress","label":"Replication stress","x":12,"y":80}],"edges":[{"from":"orc","to":"mcm","type":"activates"},{"from":"gem","to":"mcm","type":"inhibits"},{"from":"mcm","to":"cdk","type":"activates"},{"from":"cdk","to":"cmg","type":"activates"},{"from":"cmg","to":"fork","type":"activates"},{"from":"dntp","to":"fork","type":"activates"},{"from":"top1","to":"fork","type":"activates"},{"from":"onc","to":"cdk","type":"activates"},{"from":"onc","to":"stress","type":"activates"},{"from":"fork","to":"stress","type":"inhibits"}],"interventions":["Antimetabolites (5-FU, gemcitabine, methotrexate, pemetrexed, hydroxyurea, cytarabine) starve or terminate synthesis","Topoisomerase I poisons (irinotecan, topotecan) and their ADC payloads (SN-38, DXd, exatecan) trap the enzyme ahead of forks","Platinum crosslinks and alkylators block polymerases","ATR, CHK1, WEE1 inhibitors exploit the stress cancers create (see replication stress); CDC7 and POLQ inhibitors in trials"]},"route":"/pathways/dna-replication-licensing/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"},{"id":"topoisomerase-inhibitors","kind":"technology","name":"Topoisomerase-I inhibitors (and ADC payloads)","route":"/technologies/topoisomerase-inhibitors/"}],"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"cdk2","kind":"target","name":"CDK2","route":"/targets/cdk2/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"}],"drug":[{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/"},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/"},{"id":"hydroxyurea","kind":"drug","name":"Hydroxyurea (hydroxycarbamide)","route":"/drugs/hydroxyurea/"},{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/"},{"id":"topotecan","kind":"drug","name":"Topotecan","route":"/drugs/topotecan/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"}],"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"}],"term":[{"id":"dxd","kind":"term","name":"DXd","route":"/terms/dxd/"},{"id":"exatecan","kind":"term","name":"Exatecan (and derivatives)","route":"/terms/exatecan/"},{"id":"payload","kind":"term","name":"Payload (ADC)","route":"/terms/payload/"},{"id":"sn-38","kind":"term","name":"SN-38","route":"/terms/sn-38/"},{"id":"topoisomerase-i-payloads","kind":"term","name":"Topoisomerase-I inhibitor payloads","route":"/terms/topoisomerase-i-payloads/"}],"paper":[{"id":"paper-bell-annu-rev-biochem","kind":"paper","name":"DNA replication in eukaryotic cells","route":"/key-papers/paper-bell-annu-rev-biochem/"}]}}