DNA replication & DNA damage repair
DNA replication couples origin licensing, helicase loading, and replisome progression (DNA polymerases, PCNA, RFC). Stalled forks intersect BER, NER, MMR, and DSB pathways (HR/NHEJ). ATR/ATM–CHEK and p53 networks coordinate replication stress and cell fate. HR deficiency (e.g., BRCA lesions) underpins PARP synthetic lethality in oncology.
1. Key targets
Core nodes
- Replisome & elongation
MCM, GINS, CDC45 with Pol α/δ/ε and PCNA–RFC; Okazaki maturation uses FEN1, DNA2, LIG1.
- Single-strand lesion repair
BER handles small base lesions; PARP–XRCC1–LIG3 supports SSBs and replication-coupled repair.
- DSBs & checkpoints
ATM/ATR license resection or NHEJ assembly; BRCA2–PALB2–RAD51 promotes HR; p53–CDKN1A can enforce arrest.
NER & MMR
- NER: GG-NER vs TC-NER for bulky vs transcription-coupled lesions
- MMR: corrects slippage; defects link to MSI / Lynch syndrome
Pathway crosstalk
- TLS polymerases swap with replicative Pols at lesions
- Chromatin & epigenetic marks gate repair factor access
Supplement: replication & repair targets (gene symbols)
Below the overview, HGNC symbols group licensing/fork protection, elongation/Okazaki maturation, BER/SSB, NER/MMR, DSB (HR/NHEJ), and checkpoint control. Validate complex composition, splice isoforms, and cell-cycle dependence with databases/papers.
Origins & replication fork
Origin recognition & pre-replicative complex
ORC1, ORC2, ORC3, ORC4, ORC5, ORC6, CDC6, CDT1, GMNN, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, CDC45, GINS1, GINS2, GINS3, GINS4, CDC7, DBF4, DBF4B
Fork protection & checkpoint coupling (representative)
TIMELESS, TIPIN, CLSPN, TOPBP1, RAD9A, RAD1, HUS1, RAD17, ATR, ATRIP, RPA1, RPA2, RPA3, RAD51, BRCA1, BRCA2, PALB2
Elongation & maturation
DNA polymerases & primase
POLA1, POLA2, PRIM1, PRIM2, POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3, POLE4, POLH, POLK, POLI, REV1, REV3L, MAD2L2
PCNA, clamp loader & Okazaki maturation
PCNA, RFC1, RFC2, RFC3, RFC4, RFC5, RNASEH2A, RNASEH2B, RNASEH2C, FEN1, DNA2, WRN, BLM, LIG1
BER & SSB handling
BER: damage recognition & excision
UNG, SMUG1, TDG, MBD4, MPG, NEIL1, NEIL2, NEIL3, OGG1, NTHL1, APEX1, APEX2, POLB, PNKP, APTX, APLF
PARP–XRCC1 axis & SSB ligation
PARP1, PARP2, PARP3, XRCC1, LIG3, SSBP1
NER & mismatch repair
Nucleotide excision repair (GG-NER / TC-NER)
DDB1, DDB2, XPC, RAD23A, RAD23B, ERCC3, ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, CDK7, CCNH, MNAT1, ERCC5, ERCC4, ERCC1, XPA, ERCC6, ERCC8, LIG1
Mismatch repair
MSH2, MSH6, MSH3, MLH1, PMS2, PMS1, MLH3, EXO1
DSBs: HR vs NHEJ
DSB end resection & homologous recombination (representative)
ATM, CHEK2, TP53BP1, RIF1, MDC1, H2AX, BRCA1, BRCA2, PALB2, BRIP1, RAD51C, RAD51D, RAD51, RAD51B, XRCC2, XRCC3, RAD54L, RAD54B, BLM, WRN, EXO1, DNA2, RBBP8
NHEJ & alt-EJ (representative)
PRKDC, XRCC5, XRCC6, LIG4, XRCC4, NHEJ1, DCLRE1C, POLM, POLL, PARP1, POLQ, LIG3, XRCC1
Checkpoints & arrest
Replication stress & damage-induced cell-cycle control
“CHK1/CHK2” in papers usually maps to CHEK1/CHEK2 (HGNC).
TP53, MDM2, MDM4, CDKN1A, CHEK1, CHEK2, WEE1, CDC25A, CDC25C, PLK1
2. Suggested experimental readouts
For phospho readouts (γ-H2AX, p-RPA, p-CHK1), pair totals, time courses, and replication inhibitors; EdU/BrdU and comet assays are model-dependent.
- PCNA chromatin loading; RPA32 phospho sites per clone (e.g., Ser33)
- γ-H2AX foci with 53BP1/BRCA1 (DSB end-processing context)
- p-CHEK1 (e.g., Ser345), p-CHEK2 (e.g., Thr68)
- EdU labeling + DNA fiber assays (speed/stalling—protocol-specific)
3. BER vs NER vs DSB repair (functional contrast)
| Pathway | Typical substrates / triggers | Core readouts | Notes |
|---|---|---|---|
| BER | Oxidation/deamination; many SSBs | PARylation, XRCC1, POLB | Replication-coupled BER—mind PARP inhibitor sequelae. |
| NER | Dimers, bulky adducts | XPC, ERCC1–XPF, incision assays | GG-NER vs TC-NER use distinct sensors. |
| DSB (HR/NHEJ) | IR, TOP1cc, collapsed forks, nucleases | γ-H2AX, RAD51 IRIF, end-joining reporters | HR favors S/G2 with resection; NHEJ often G1-biased (simplified). |
4. Translational & clinical context
- HRD / PARPi: HR deficiency (BRCA1/2, PALB2, etc.) enables PARPi synthetic lethality—pair genomics/functional assays.
- MSI / MMRd: MMRd tumors have distinct immunotherapy contexts; IHC for MLH1/PMS2/MSH2/MSH6 is common.
- ATR / WEE1: Replication-stress targeting in high-burden tumors—project/toxicity dependent.
DNA replication & repair–related antibodies (curated)
5. Product lines & on-site search
Primary & phospho antibodies
PCNA, MCM, RPA, p-CHEK1/2, γ-H2AX, RAD51, 53BP1, BRCA1/2, PARP, MMR proteins—WB/IF/IHC/ChIP as applicable.
Recombinant proteins / enzymes
Repair subunits / polymerase domains for biochemical reconstitution—availability/datasheet dependent.
Assays & functional reagents
Viability, apoptosis, DDR ELISA kits—research use; ethics/biosafety.
Quick search (site)
6. Inhibitors & tool compounds (summary)
For research use; follow SOP, datasheets, ethics. Some agents are clinical drugs—regulatory sourcing rules apply.
PARP trapping / synthetic lethality probes.
ATR inhibitors; replication-stress/checkpoint studies.
ATM inhibitor; early DSB response dissection.
DNA-PKcs inhibition; NHEJ/end-joining readouts.
MRE11-related end-processing tool—dose/off-target caution.
Replication stress inducers—model-dependent.
7. Pathway schematic
- Licensing → replisome elongation
- Fork stall → ATR–RPA–CHK1 axis
- BER/NER/MMR handle lesion classes
- DSBs: HR vs NHEJ competition/cooperation
8. Pathway biology overview
Genome fidelity requires spatiotemporal coordination of replication and repair—HR vs NHEJ bias shifts with cell-cycle state; chromatin, transcription, and nuclease activity shape lesion fate. Radiotherapy and many chemotherapeutics exploit replication–repair vulnerabilities.
- Licensing couples to CDK activity—often dysregulated in cancer
- Telomeric/mtDNA maintenance partly shares nuclear DDR factors
9. Related pathways on this site
10. External databases & modification resources
11. References
Replication & replication stress
- • Zeman MK, Cimprich KA. (2014). Nat Rev Genet. 15(3):174-87.
- • Gaillard H, García-Muse T, Aguilera A. (2015). Nat Rev Mol Cell Biol. 16(4):207-20.
DSB repair & cancer targeting
- • Lord CJ, Ashworth A. (2017). Nat Rev Cancer. 17(7):387-395.
- • Curtin NJ. (2005). Mol Cancer Ther. 4(11):1425-35.