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PNKP, a 57-kDa
protein, is a dual function enzyme that
possesses DNA 3?-phosphatase and DNA 5?-kinase activities (86, 87). The location of the gene for PNKP was found
to be at chromosome 19q13.4 (88). PNKP is found in both the nucleus and
mitochondria. PNKP participates in the BER/SSBR pathway to process the damaged
ends of nuclear and mitochondrial DNA caused by oxidative damage (89). Under normal conditions, PNKP is regulated
by a balance between PNKP transcription and CUL4A-DDB1-STRAP-dependent protein
degradation (90). However, the activation of ATM upon
cellular exposure to radiation and oxidative stress prevents PNKP
ubiquitylation and degradation by phosphorylation at serines 114 and 126 in the
linker region between the FHA and catalytic domains of PNKP (91).

The
phosphatase 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 instead
acts on RNA (93, 94). Identified proteins of Caenorhabditis elegans and Schizosaccharomyces
pombe have ~ 30% similarity to human PNKP (88, 95-97). The murine PKNP is ~80% identical to human
PNKP (93).

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A crystal
structural of murine PNKP (Figure 1.4) revealed that the enzyme is composed of
three domains, the kinase domain at the C-terminus, the
phosphatase domain in the centre and an FHA domain at the N-terminus (98,
99). The kinase and phosphatase domains together make up the catalytic
segment of PNKP, once separated they lose activity (100).  The
flexibility of the kinase and phosphatase domains of PNKP may allow this enzyme
to work on either the 5?-OH or 3?-phosphate termini, or both if present at the
same DNA strand break (99). The FHA domain, a phosphothreonine-binding
signaling module, is attached to the catalytic fragment by a flexible linker.
The FHA domain recognizes the phosphorylated forms of XRCC1/4, key components
of BER and NHEJ pathways, respectively, to direct PNKP to the site of DNA
damage. This recognition occurs via FHA-dependent
interaction with CK2-phosphorylated regions of XRCC 1/4 (101,
102).

 

 

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