Literature summary extracted from

Weinfeld, M.; Mani, R.S.; Abdou, I.; Aceytuno, R.D.; Glover, J.N.
Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair (2011), Trends Biochem. Sci., 36, 262-271.

Activating Compound

EC Number	Activating Compound	Comment	Organism	Structure
2.7.1.78	XRCC1	mechanism underlying XRCC1-induced stimulation of PNKP, XRCC1 displaces PNKP from the reaction product, and addition of XRCC1 increases PNKP enzymatic turnover	Homo sapiens
2.7.1.78	XRCC1	mechanism underlying XRCC1-induced stimulation of PNKP, XRCC1 displaces PNKP from the reaction product, and addition of XRCC1 increases PNKP enzymatic turnover. Phosphorylation of XRCC1 by CK2 stimulates the kinase and phosphatase activities of PNKP	Mus musculus
2.7.1.78	XRCC4	-	Mus musculus
2.7.1.78	XRCC4	-	Homo sapiens
3.1.3.32	XRCC1	DNA repair scaffold protein, mechanism, overview	Mus musculus
3.1.3.32	XRCC1	DNA repair scaffold protein, mechanism, overview	Homo sapiens
3.1.3.32	XRCC4	DNA repair scaffold protein, mechanism, overview	Mus musculus
3.1.3.32	XRCC4	DNA repair scaffold protein, mechanism, overview	Homo sapiens

Application

EC Number	Application	Comment	Organism
3.1.3.32	pharmacology	PNKP, similar to several other DNA repair proteins, is of increasing clinical interest owing to the identification of small molecule inhibitors of these enzymes that sensitize cells to IR or chemotherapeutic agents	Homo sapiens

Crystallization (Commentary)

EC Number	Crystallization (Comment)	Organism
2.7.1.78	crystal structure determination and analysis	Mus musculus

Natural Substrates/ Products (Substrates)

EC Number	Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
2.7.1.78	additional information	Mus musculus	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP forkhead-associated domain to phosphorylated motifs on XRCC1 and XRCC4, overview	?	-	?
2.7.1.78	additional information	Homo sapiens	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP forkhead-associated domain to phosphorylated motifs on XRCC1 and XRCC4, overview. Phosphorylation-independent interaction between PNKP and XRCC1 in human cells, since a non-phosphorylated XRCC1S518A/T519A/T523A triple mutant is also bound	?	-	?
3.1.3.32	additional information	Homo sapiens	structure of the human PNKP FHA domain bound to a doubly phosphorylated phosphopeptide derived from XRCC1, overview	?	-	?

Organism

EC Number	Organism	UniProt	Comment	Textmining
2.7.1.78	Homo sapiens	-	-	-
2.7.1.78	Mus musculus	-	-	-
2.7.1.78	Schizosaccharomyces pombe	-	-	-
2.7.1.78	Tequatrovirus T4	-	-	-
3.1.3.32	Homo sapiens	-	-	-
3.1.3.32	Mus musculus	-	-	-

Source Tissue

EC Number	Source Tissue	Comment	Organism	Textmining
3.1.3.32	HeLa cell	-	Homo sapiens	-

Substrates and Products (Substrate)

EC Number	Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
2.7.1.78	additional information	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP forkhead-associated domain to phosphorylated motifs on XRCC1 and XRCC4, overview	Mus musculus	?	-	?
2.7.1.78	additional information	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP forkhead-associated domain to phosphorylated motifs on XRCC1 and XRCC4, overview. Phosphorylation-independent interaction between PNKP and XRCC1 in human cells, since a non-phosphorylated XRCC1S518A/T519A/T523A triple mutant is also bound	Homo sapiens	?	-	?
3.1.3.32	additional information	structure of the human PNKP FHA domain bound to a doubly phosphorylated phosphopeptide derived from XRCC1, overview	Homo sapiens	?	-	?

Subunits

EC Number	Subunits	Comment	Organism
2.7.1.78	More	PNKP is a multi-domain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains	Homo sapiens
2.7.1.78	More	PNKP is a multi-domain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains. The forkhead-associated domain is linked to the catalytic domain through a flexible polypeptide segment and acts to selectively bind acidic casein kinase 2-phosphorylated regions in XRCC1 and XRCC4, which are key scaffolding proteins in the repair of DNA single and double strand breaks, respectively. Two catalytic active sites are positioned on the same side of the protein	Mus musculus
2.7.1.78	More	PNKP is a multi-domain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains. The forkhead-associated domain is linked to the catalytic domain through a flexible polypeptide segment and acts to selectively bind acidic casein kinase 2-phosphorylated regions in XRCC1 and XRCC4, which are key scaffolding proteins in the repair of DNA single and double strand breaks, respectively. Two catalytic active sites are positioned on the same side of the protein	Tequatrovirus T4
3.1.3.32	More	PNK phosphatase is a multidomain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains, structure of mammalian PNK phosphatase, overview	Mus musculus
3.1.3.32	More	PNK phosphatase is a multidomain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains, structure of mammalian PNK phosphatase, overview	Homo sapiens

Synonyms

EC Number	Synonyms	Comment	Organism
2.7.1.78	Pnk1	-	Schizosaccharomyces pombe
2.7.1.78	PNKP	-	Mus musculus
2.7.1.78	PNKP	-	Homo sapiens
2.7.1.78	PNKP	-	Tequatrovirus T4
2.7.1.78	polynucleotide kinase/phosphatase	-	Mus musculus
2.7.1.78	polynucleotide kinase/phosphatase	-	Homo sapiens
2.7.1.78	polynucleotide kinase/phosphatase	-	Schizosaccharomyces pombe
2.7.1.78	polynucleotide kinase/phosphatase	-	Tequatrovirus T4
3.1.3.32	PNKP	-	Mus musculus
3.1.3.32	PNKP	-	Homo sapiens
3.1.3.32	polynucleotide kinase/phosphatase	-	Mus musculus
3.1.3.32	polynucleotide kinase/phosphatase	-	Homo sapiens

Cofactor

EC Number	Cofactor	Comment	Organism	Structure
2.7.1.78	ATP	-	Schizosaccharomyces pombe
2.7.1.78	ATP	the ATP binding site is defined by the Walker A (P-loop) and B motifs conserved in various kinases, as well as an Asp residue that activates the 5'-OH for attack on the ATP gamma-phosphate	Tequatrovirus T4
2.7.1.78	ATP	the ATP binding site is defined by the Walker A (P-loop) and B motifs conserved in various kinases, as well as an Asp396 that activates the 5'-OH for attack on the ATP gamma-phosphate	Mus musculus
2.7.1.78	ATP	the ATP binding site is defined by the Walker A (P-loop) and B motifs conserved in various kinases, as well as an Asp396 that activates the 5'-OH for attack on the ATP gamma-phosphate	Homo sapiens

General Information

EC Number	General Information	Comment	Organism
2.7.1.78	malfunction	Pnk1 deletion in fission yeast renders cells sensitive to camptothecin	Schizosaccharomyces pombe
2.7.1.78	malfunction	PNKP depletion in human cells renders cells sensitive to camptothecin. A small molecule inhibitor of PNKP phosphatase activity enhances the sensitivity of cells to IR and camptothecin. Enzyme mutational defects can cause neurological disorders with various symptoms, e.g. a severe neurological autosomal recessive disease characterized by microcephaly, intractable seizures and developmental delay	Homo sapiens
2.7.1.78	additional information	molecular architecture of the enzyme, overview. The mammalian enzyme preferentially phosphorylates 5'-hydroxyl termini within nicked, gapped or double-strand breaks with single-stranded 3'-overhanging ends, whereas single-stranded 5'-termini or blunt double-stranded ends are phosphorylated less efficiently. The selective recognition of the larger, double-stranded DNA substrates is effected by a broad DNA recognition groove composed of two distinct positively charged surfaces. Mechanisms of single-strand break and double-strand break repairs, and of base excision repair, overview	Homo sapiens
2.7.1.78	additional information	molecular architecture of the enzyme, overview. The mammalian enzyme preferentially phosphorylates 5'-hydroxyl termini within nicked, gapped or DSBs with single-stranded 3' overhanging ends, whereas single-stranded 5'-termini or blunt double-stranded ends are phosphorylated less efficiently. The selective recognition of the larger, double-stranded DNA substrates is effected by a broad DNA recognition groove composed of two distinct positively charged surfaces. Mechanisms of single-strand break and double-strand break repairs, and base excision repair, overview	Mus musculus
2.7.1.78	additional information	molecular architecture of the enzyme, overview. The phage PNK DNA binding cleft forms a narrow channel leading to the conserved catalytic aspartic acid residue that accommodates single-stranded, but not double-stranded, substrates. Mechanisms of single-strand break and double-strand break repairs, overview	Tequatrovirus T4
2.7.1.78	physiological function	polynucleotide kinase/phosphatase is an essential enzyme for the repair of damaged DNA termini. PNKP possesses both 5'-kinase and 3'-phosphatase activities that are frequently required for processing of single- and double-strand break termini	Mus musculus
2.7.1.78	physiological function	polynucleotide kinase/phosphatase is an essential enzyme for the repair of damaged DNA termini. PNKP possesses both 5'-kinase and 3'-phosphatase activities that are frequently required for processing of single- and double-strand break termini	Homo sapiens
2.7.1.78	physiological function	polynucleotide kinase/phosphatase is an essential enzyme for the repair of damaged DNA termini. PNKP possesses both 5'-kinase and 3'-phosphatase activities that are frequently required for processing of single- and double-strand break termini	Schizosaccharomyces pombe
2.7.1.78	physiological function	polynucleotide kinase/phosphatase is an essential enzyme for the repair of damaged DNA termini. PNKP possesses both 5'-kinase and 3'-phosphatase activities that are frequently required for processing of single- and double-strand break termini	Tequatrovirus T4
3.1.3.32	malfunction	mutations that lead to alterations in PNKP, similar to mutations in genes encoding other strand break repair proteins, are associated with a severe autosomal recessive neurological disorder	Homo sapiens
3.1.3.32	additional information	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP FHA domain to phosphorylated motifs on XRCC1 and XRCC4, overview	Homo sapiens
3.1.3.32	additional information	PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP FHA domain to phosphorylated motifs on XRCC1 and XRCC4, overview. The crystal structure of murine PNKP shows that the two catalytic active sites are positioned on the same side of the protein	Mus musculus
3.1.3.32	physiological function	polynucleotide kinase/phosphatase serves a crucial role in the repair of DNA strand breaks by catalyzing the restoration of 5'-phosphate and 3'-hydroxyl termini. It is involved in single-strand break repair and participates in several DNA repair pathways through interactions with other DNA repair proteins, notably XRCC1 and XRCC4, regulation and enzyme recruitment, overview. Physiological importance of PNKP in maintaining the genomic stability of normal tissues, particularly developing neural cells, as well as enhancing the resistance of cancer cells to genotoxic therapeutic agents. The enzyme also performs base excision and double-strand break repair, overview	Mus musculus
3.1.3.32	physiological function	polynucleotide kinase/phosphatase serves a crucial role in the repair of DNA strand breaks by catalyzing the restoration of 5'-phosphate and 3'-hydroxyl termini. It is involved in single-strand break repair and participates in several DNA repair pathways through interactions with other DNA repair proteins, notably XRCC1 and XRCC4, regulation and enzyme recruitment, overview. Physiological importance of PNKP in maintaining the genomic stability of normal tissues, particularly developing neural cells, as well as enhancing the resistance of cancer cells to genotoxic therapeutic agents. The enzyme also performs base excision and double-strand break repair, overview	Homo sapiens

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Release 2023.1 (January 2023)