DNA Damage Response and Repair

Canonical source: hsa03400

Pathway Overview

The DNA damage response (DDR) pathway detects and repairs DNA lesions to maintain genomic integrity. Double-strand breaks activate ATM/ATR kinases, which phosphorylate effectors including p53 (TP53). TP53 induces cell cycle arrest, DNA repair, or apoptosis. BRCA1 and BRCA2 function in homologous recombination repair; mutations cause hereditary breast and ovarian cancer. BRCA1/2 proteins stabilize stalled replication forks and promote error-free repair. TP53 mutations are common in cancers and Li-Fraumeni syndrome. UV radiation and endogenous replication stress trigger the pathway. EGFR signaling can suppress apoptosis and interact with DDR. Defective repair leads to mutation accumulation and cancer.

Environmental Triggers

ExposureTrigger type
uv-radiationDirect DNA damage; cyclobutane dimers and 6-4 photoproducts activate DDR
tobaccoCarcinogens cause adducts and double-strand breaks; oxidative stress
heavy-metalsOxidative stress and DNA damage; arsenic is carcinogenic

Genetic Modulation Points

Key genes

  • brca1— Homologous recombination; DNA end resection; replication fork protection; tumor suppressor
  • brca2— Recruits RAD51 for strand invasion; homologous recombination; replication fork stability
  • tp53— Transcription factor; cell cycle arrest, DNA repair, apoptosis; guardian of genome
  • egfr— Growth signaling; can suppress apoptosis; mutations common in lung cancer

Regulatory checkpoints

  • DNA damage sensing— tp53Therapeutic target
  • Homologous recombination— brca1, brca2Therapeutic target

Tissue Specificity

breast epithelium— BRCA1/2 loss drives breast cancer
colorectal epithelium— TP53 mutations in colorectal cancer
lung— EGFR and TP53 in lung cancer

Disease Relevance

Linked diseases

  • breast-cancer— BRCA1/2 mutations cause hereditary breast cancer; pathway defects common in sporadic cases
  • colorectal-cancer— TP53 mutations and mismatch repair defects; chromosomal instability
  • lung-cancer— TP53 and EGFR mutations; tobacco-induced damage

Linked exposures

  • uv-radiation— UV causes lesions requiring nucleotide excision repair; TP53 mutations in skin cancer
  • endocrine-disruptors— Estrogenic compounds may interact with BRCA pathway in breast cancer

Pathway Diagram

Pathway diagram placeholder. A visual representation of this pathway will be integrated when available.

Evidence Nodes

Evidence for this pathway is derived from:

  • 3 environmental trigger(s)
  • 4 key gene(s)
  • 3 linked disease(s)
  • 2 linked exposure(s)

References

  1. 1.Roy R, et al. (2012). BRCA1 and BRCA2 in DNA repair. Nature Reviews Molecular Cell Biology. doi:10.1038/nrm3251
  2. 2.Levine AJ, Oren M (2009). TP53 and cancer. Nature Reviews Cancer. doi:10.1038/nrc2723
  3. 3.Brash DE (2015). DNA damage and UV radiation. Journal of Investigative Dermatology. doi:10.1038/jid.2015.219
  4. 4.Narod SA, et al. (2015). Hereditary breast cancer: BRCA and beyond. Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2015.125