PNKP, a 57-kDaprotein, is a dual function enzyme thatpossesses DNA 3?-phosphatase and DNA 5?-kinase activities (86, 87). The location of the gene for PNKP was foundto be at chromosome 19q13.4 (88).

PNKP is found in both the nucleus andmitochondria. PNKP participates in the BER/SSBR pathway to process the damagedends of nuclear and mitochondrial DNA caused by oxidative damage (89). Under normal conditions, PNKP is regulatedby a balance between PNKP transcription and CUL4A-DDB1-STRAP-dependent proteindegradation (90). However, the activation of ATM uponcellular exposure to radiation and oxidative stress prevents PNKPubiquitylation and degradation by phosphorylation at serines 114 and 126 in thelinker region between the FHA and catalytic domains of PNKP (91). Thephosphatase activity of PNKP takes precedence over the kinase activity (92). Phage T4 PNK, another bifunctional enzyme,shares similar catalytic activity to PNKP but lacks an FHA domain (93). T4 PNK does not repair DNA, but insteadacts on RNA (93, 94). Identified proteins of Caenorhabditis elegans and Schizosaccharomycespombe have ~ 30% similarity to human PNKP (88, 95-97).

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The murine PKNP is ~80% identical to humanPNKP (93).A crystalstructural of murine PNKP (Figure 1.4) revealed that the enzyme is composed ofthree domains, the kinase domain at the C-terminus, thephosphatase domain in the centre and an FHA domain at the N-terminus (98,99). The kinase and phosphatase domains together make up the catalyticsegment of PNKP, once separated they lose activity (100).  Theflexibility of the kinase and phosphatase domains of PNKP may allow this enzymeto work on either the 5?-OH or 3?-phosphate termini, or both if present at thesame DNA strand break (99). The FHA domain, a phosphothreonine-bindingsignaling module, is attached to the catalytic fragment by a flexible linker.

The FHA domain recognizes the phosphorylated forms of XRCC1/4, key componentsof BER and NHEJ pathways, respectively, to direct PNKP to the site of DNAdamage. This recognition occurs via FHA-dependentinteraction with CK2-phosphorylated regions of XRCC 1/4 (101,102).   


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