Table 2.
Function of important enzymes/proteins involved in the major DNA repair pathways.
| Enzyme/ Protein | Function |
|---|---|
| DDS Pathway | |
| ATM (ataxia-telangiectasia mutated) | Cell cycle checkpoint kinase protein, which belongs to the PI3/PI4- kinase family. Serves as a DNA damage sensor and regulator of a wide variety of downstream proteins, including, 1) Tumour suppressor protein p53 and 2) Serine/threonine protein kinase that activates checkpoint signalling upon double strand breaks (DSBs), apoptosis, and genotoxic stresses. |
| ATR Rad3-related kinase | PI3 kinase-related kinase family member (like ATM), which phosphorylates multiple substrates on serine/ threonine residues (that are followed by a glutamine) in response to DNA damage or replication blocks. Causes cell cycle delay, in part, by phosphorylating checkpoint kinase (CHK)1, CHK2, and p53. |
| CHK1 and CHK2 (Checkpoint kinase 1 and 2) | Downstream protein kinases of ATM/ATR, which play an important role in DNA damage checkpoint control. |
| BER Pathway | |
| APEX1 (Apurinic/apyrimidinic endonuclease 1) | Multifunctional DNA repair enzyme, apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) responsible for abasic site cleavage activity. Plays a critical role in the DNA base excision repair (BER) pathway and in the redox regulation of transcriptional factors. Activated/ induced by oxidative DNA damage. Localisation signals, post-translational modifications and dynamic regulation determines the localisation of APE protein in the nucleus with subcellular localization in the mitochondria, endoplasmic reticulum and cytoplasm. |
| APEX2 (Apurinic/apyrimidinic endonuclease 2) | AP endonuclease 2 is characterized by a weak AP endonuclease activity, 3′-phosphodiesterase activity and 3′- to 5′-exonuclease activity. Involved in removal of mismatched 3′-nucleotides from DNA and ATR-Chk1 checkpoint signalling in response to oxidative stress. |
| (POLB) DNA polymerase β | Contributes to DNA synthesis and deoxyribose-phosphate removal. |
| (FEN1) Flap endonuclease 1 | Possesses 5′–3′ exonuclease activity and cleaves 5′ overhanging “flap structures” in DNA replication and repair. |
| LIG1 (Ligase 1) | Seals SSB ends. |
| MBD4 (methyl-CpG binding domain protein 4) | Belongs to a family of nuclear proteins that possess a methyl-CpG binding domain (MBD). These proteins bind specifically to methylated DNA, possess DNA N-glycosylase activity and can remove uracil or 5-fluorouracil in G:U mismatches. |
| MUTYH (mutY DNA glycosylase) | Serves as DNA glycosylase (excises adenine mispaired with 8-oxoguanine). Maintains chromosome stability by inducing ATR-mediated checkpoint activation, cell cycle arrest and apoptosis. |
| NEIL1, NEIL3 (Nei-like 1; Nei-like 3) | Generate apurinic/apyrimidinic (AP) sites and/or SSBs with blocked ends. |
| NTHL1 | Serve as oxidized base-specific DNA glycosylases that remove oxidized and/or mismatched DNA bases. |
| OGG1 (8-oxoguanine DNA glycosylase) | Excises and repairs oxidatively damaged guanine bases in DNA, which occur as a result of exposure to ROS. |
| PCNA (Proliferating cell nuclear antigen) | Co-factor for DNA polymerase and essential for DNA synthesis and repair. |
| PARP1 (Poly ADP ribose polymerase) | PARP1—serves as sensor of SSBs. |
| XRCC1 (X-ray repair cross-complementing protein 1) | XRCC1—serves as a scaffold for recruiting and activating BER proteins. |
| NER Pathway | |
| RPA1 (replication protein A1) | Largest subunit of the replication protein A (RPA), the heterotrimeric single-stranded DNA-binding protein involved in replication, repair, recombination and DNA damage check point activation. |
| XPC (xeroderma pigmentosum group C protein) | Recognizes bulky DNA adducts. Pairs up with RAD23 and helps in the assembly of the other core proteins involved in NER pathway progression. |
| XPA (xeroderma pigmentosum group A protein) | Attaches to damaged DNA, interacts along with other proteins in the NER pathway to unwind, excise and replace the damaged DNA. |
| HRR Pathway | |
| BRCA1/ BRCA2 (breast cancer type 1 and type 2 susceptibility proteins) | BRCA1 and BRCA2 are coded by human tumour suppressor genes that are involved in DNA damage repair, cell cycle progression, transcription, ubiquitination and apoptosis. Aberrant proteins coded by mutated genes are found in hereditary breast and ovarian cancers; activation of various kinases in response to DNA-damage have been shown to phosphorylate sites on BRC1 and BRC2 in a cell cycle-dependent manner. |
| RAD51 | Involved in the homologous recombination and repair of double strand DNA breaks. |
| NHEJ Pathway | |
| Ku | Ku, a heterodimer of two related proteins, Ku70 and Ku80, is involved in DSB repair and V(D)J recombination. |
| LIG4 (Ligase 4) | LIG4 is the DNA ligase required for, and specific to, c-NHEJ. It catalyzes the same ATP-dependent transfer of phosphate bonds that results in strand ligation in all eukaryotic DNA repair. LIG4 is the only ligase with the mechanistic flexibility to ligate one strand independently of another or to ligate incompatible DSB ends as well as gaps of several nucleotides. |
| XRCC4 (X-ray repair cross-complementing protein 1) | XRCC4 is a non-enzymatic protein that is required for the conformational stability and functioning levels of LIG4. XRCC4 interacts with LIG4 facilitated by carboxy-terminal repeats at the LIG4 carboxyl terminus, resulting in a coiled-coil like conformation. Most of the enzymatic domain of LIG binds to and interacts with XRCC4, except for the small region implicated in DNA binding. |