Table 1.
DDR-proteins mutations associated to various cancers.
| DDR Proteins | DDR Signaling Pathways | Protein Activity/Function | Cancer-Associated Mutations * |
|---|---|---|---|
| ATM | Cell cycle regulators | Kinases | Breast, colon, endometrial, leukemia, lung, lymphoma, pancreatic, prostate |
| ATR | Breast, colon, endometrial, gastric, lung, lymphoma | ||
| CHK2 | Cell cycle | Phosphatases | Bladder, breast, colon, endometrial, lung |
| APC-C/CDH1 | Breast, gastric, lung | ||
| PTEN | Cell death | Phosphatase | Breast, endometrial, gastric |
| P53 | Transcription factor | Found in 39.52% of all cancers (AACR) | |
| DNA repair proteins | DNA repair pathways | ||
| Ku70/Ku80 | NHEJ | Helicases | Breast, colorectal, lung, melanoma |
| DNA-PK | Kinase | Breast, colon, glioma, oesophagal, lung | |
| NBS1 | HR | MRN complex | Breast, colon, esophageal, head and neck, hepatoma, liver, lung, lymphoma, prostate |
| MRE11 | Breast | ||
| RAD50 | Colon, gastrointestinal, lung | ||
| BRCA1 | E3 ubiquitin-ligase | Breast, colon, gastrointestinal, haematological, lung, melanoma, ovarian, pancreatic, prostate | |
| BRCA2 | RAD51 binding to DNA | ||
| PALB2/FANCN | Recruitment of BRCA2 and RAD51 | Breast, colon, head and neck, lung, ovarian | |
| FANCA, FANCB | FA repair complex | Breast, colon, leukemia, liver, lung | |
| FANCO/RAD51C | DNA-dependent ATPase | Breast, colon, lung, ovarian, prostate | |
| RAD51D | Breast, lung, ovarian | ||
| BLM | Helicases | Breast, colon, endometrial, leukemia, lung, lymphoma, melanoma | |
| WRN | Colorectal, endometrial, lung, melanoma, pancreatic, thyroid | ||
| ERCC1 | NER | Nuclease | Colorectal, glioma, lung, skin |
| XPA, XPC | Scaffold protein | Bladder, colon, lung, skin | |
| XPD/ERCC2 | Helicase | ||
| XPG/ERCC5 | Endonuclease | ||
| OGG1 | BER | Glycosylase | Breast, lung, renal |
| PARP1 | ADP-ribosyltransferase | Breast, colon, endometrial, lung | |
| XRCC1 | Scaffold protein | Non-small cell lung | |
| MLH1 | MMR | ATPase | Brain, breast, colorectal, endometrial, hepatobiliary, lung, ovarian, pancreatic, skin, stomach, upper urinary |
| MSH2, MSH6 | Scaffold protein | ||
| MGMT | DR | Methyltransferase | Gliomas |
Notes for Table 1: ATM, ATR, CHK1/2, and APC/C-CDH1 are involved in cell cycle regulation; PTEN and P53 in programmed cell death. In NHEJ, the ATP dependent helicases Ku70 and Ku80 form a heterocomplex with DNA-ends, and Ku80 C terminus recruits DNA-PK, a phosphatidylinositol 3-kinase related serine/threonine kinase [211]. In HR, two NBS1 subunits (phosphopeptide-binding Nijmegen breakage syndrome protein 1) are associated with two MRE11 subunits (meiotic recombination 11 homolog 1), and two ATP-binding cassette (ABC)-ATPase (RAD50) to compose the MRN complex [212]. BRCA1, an E3 ubiquitin ligase, and BRCA2 facilitate response to DNA damage. PALB2/FANCN (partner and localizer of BRCA2) has a critical role through the recruitment of BRCA2 and RAD51 to DNA breaks [213]. FANCA and FANCB are associated with other FANC (Fanconi Anaemia) and FAAP (FA-associated proteins) (FANCC, FANCE, FANCF, FANCG, FANCL, FANCM and FAAP20, FAAP24, and FAAP100). They form the FA core complex carrying an E3 ligase activity to monoubiquitinate FANCI and FANCD2 [214], and initiate DNA repair by forming a platform to recruit additional proteins. RAD51C forms distinct complexes, one with a related DNA-dependent ATPase paralog, RAD51D, forming the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2), and one with the CX3 complex (RAD51C-XRCC3) [215]. BLM (Bloom syndrome protein) and WRN (Werner syndrome ATP-dependent helicase) are members of the RecQ helicase family. WRN also displays a 3′ to 5′ exonuclease activity [216]. In NER, ERCC1 has a nuclease activity involved in DNA excision repair. XPD/ERCC2 is a 5′–3′ DNA helicase, XPG/ERCC5 an endonuclease involved in DNA excision repair, and XPA (Xeroderma pigmentosum complementation group A) a zing finger protein involved in nucleotide excision repair [217]. In BER, OGG1 is a 8-Oxoguanine glycosylase and the primary enzyme of the process [218]. PARP1 the poly(ADP-ribose) polymerase 1 binds to damaged chromatin and recruits XRCC1 (X-ray repair cross-complementing protein 1) that interacts with DNA ligase III acting as a scaffold protein [219]. MMR is initiated by MutS α (MSH2–MSH6) or MutS β (MSH2–MSH3) binding to a dsDNA mismatch, before MLH MutL alpha (MLH1-PMS2) is recruited to the heteroduplex. MSH2 seems to act as a scaffold, MSH6 has a DNA-dependent ATPase activity, and MLH1 has a nucleotide-binding capability [220]. The O-6-méthylguanine-DNA-méthyltransférase, MGMT, carries out direct repair (DR) of alkylated DNA *: [204,221].