DNA replication & origin licensing
Before a cell divides it must copy three billion letters of DNA exactly once. It does this by 'licensing' thousands of start points in advance and then firing them in waves. Cancers fire too many too fast, and many chemotherapies work by starving or jamming the copying machinery.
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.
In one picture
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.
Diagram
top- 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
Pages like this
not linked directly; found by shared links- PathwayDrug efflux pumps (ABC transporters)
Shares SN-38, Exatecan (and derivatives), DXd, Sacituzumab govitecan and the tags mechanism, mechanics-atlas.
- PathwayBase excision repair, PARP & alkylation damage
Shares ATR, DNA replication stress, DNA damage response & homologous recombination, Cytotoxic chemotherapy and the tags mechanism, mechanics-atlas.
- PathwayDouble-strand break repair: HR versus end joining
Shares ATR, DNA replication stress, DNA damage response & homologous recombination, Platinum agents and the tags mechanism, mechanics-atlas.
- PathwaySynthetic lethality: paired dependencies
Shares ATR, DNA replication stress, DNA damage response & homologous recombination and the tags mechanism, mechanics-atlas.
- PathwayMitosis & the spindle assembly checkpoint
Shares The cell-cycle engine (cyclins & CDKs), HER2, Cytotoxic chemotherapy, Antibody-drug conjugate (ADC) and the tags mechanism, mechanics-atlas.
- PathwayThe p53 network (guardian of the genome)
Shares ATR, DNA replication stress and the tags mechanism, mechanics-atlas.
- PathwayGlutamine addiction
- PathwayReceptor tyrosine kinase activation
Shares Trastuzumab deruxtecan, KRAS, HER2, Antibody-drug conjugate (ADC) and the tags mechanism, mechanics-atlas.