1.
Tissue specific DDR and tumorigenesis
| Tissue | DNA damaging agents | DNA damage | Major DDR | Common mutations in DDR and repair pathway | Tumorigenesis or related diseases |
| UV, ultraviolet; NER, nucleotide excision repair; XP, xeroderma pigmentosum; CS, Cockayne syndrome; TTD, trichothiodystrophy; ROS, reactive oxygen species; SSB, single strand break; BER, base excision repair; HBV, hepatitis B virus; HCV, hepatitis C virus; AFB1, Aflatoxin B1; RNS, reactive nitrogen species; HR, homologous recombination; NHEJ, non-homologous end joining; MMR, mismatch repair; HCC, hepatocellular carcinoma; IDL, insertion-deletion loop; MSI, microsatellite instability; CRC, colorectal cancer; CIMP, CpG island methylator phenotype; CE, catechol estrogen; SQ, semiquinone; Q, quinone; DSB, double strand break; IR, ionizing radiation; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia. | |||||
| Skin | Sunlight (e.g., UV-B, UV-A) | Direct DNA photolesions (e.g., (6,4)-photoproducts, cyclobutane pyrimidine dimers) | NER | XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), POLH (XPV) | XP |
| ERCC8 (CSA), ERCC6 (CSB), XPB, XPD, XPG | CS | ||||
| TTDA, XPB, XPD | TTD | ||||
| XPA, XPC, XPE, XPF | Cutaneous neoplasms | ||||
| ROS (e.g., hydrogen peroxide, hydroxyl radicals, superoxide anions) | Oxidative lesions, SSBs | BER | LIG1 | Skin maladies | |
| Liver | HBV and HCV infection, aflatoxins (e.g., AFB1), ROS, RNS | DNA adducts, oxidative lesions, genetic and epigenetic abnormalities | HR, NHEJ, NER, BER, MMR | p53, XRCC1, OGG1, ATM, MRE11A, RAD50, NBN, PARP1 | HCC |
| Pancreas | ROS (e.g., HOCl, O2·–, NO), RNS (e.g., NO2·, ONOOCO2–) | Aromatic DNA adducts, oxidative lesions (e.g., 2-deoxyribose oxidation, nitration and oxidation of dG), SSBs, DSBs | BER, HR | BRCA2, PALB2, ATM, DNA-PK, CHK1, CHK2, FANCC, FANCG | Chronic pancreatitis, pancreatic cancer |
| Colon | Replication errors, gut microbiota, inflammation, ROS | Mismatches, IDLs, frameshift or missense mutations | MMR | MLH1, MSH2, MSH6, PMS2 | MSI, CRCs (e.g., Lynch syndrome, CIMP) |
| Breast and ovary | Estrogens and their metabolites (CE-SQs, CE-Qs) | Oxidative lesions, depurinating adducts (e.g., 4-OHE-1-N3Ade, 4-OHE-1-N7Gua, 2-OHE-6-N3Ade), DSBs | HR | BRCA1, ATM, CHEK2, PALB2, BARD1, BRIP1, RAD50, RAD51C, RAD51D, NBN, FANCM, MRE11 | Breast cancer, ovarian cancer |
| Hematopoietic system | IR exposure, ROS, replication errors | DSBs, SSBs | HR, NHEJ, BER | IDH1, p53, Bcl2, Bcl-Xl, Mcl1, A1, Bax, Noxa, Puma, p21 | AML, CLL |