2008
DOI: 10.1074/jbc.m802246200
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Mitotic Phosphorylation Stimulates DNA Relaxation Activity of Human Topoisomerase I

Abstract: Human DNA topoisomerase I (topo I) is an essential mammalian enzyme that regulates DNA supercoiling during transcription and replication. In addition, topo I is specifically targeted by the anticancer compound camptothecin and its derivatives. Previous studies have indicated that topo I is a phosphoprotein and that phosphorylation stimulates its DNA relaxation activity. and Ser 394 can be phosphorylated by Cdk1. When wild type topo I was pulled down from mitotic cells and dephosphorylated with alkaline phospha… Show more

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Cited by 16 publications
(26 citation statements)
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“…Furthermore, the underphosphorylated and less active form of topo I in H23 cells can be activated by CK2 treatment in vitro, consistent with a possible role for CK2 in regulating cellular sensitivity to camptothecin (6). Phosphorylation of serine 21 by PKC has been found to promote increased sensitivity of topo I to camptothecin (22), consistent with a previous study showing that PKC enhances the sensitivity of the enzyme to camptothecin (16). Taken together, these observations suggest that one or more topo I serine phosphorylating activities could have a general role in a variety of cancers to regulate topo I activity in vivo in ways that affect the cellular response to camptothecin-related drugs.…”
supporting
confidence: 89%
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“…Furthermore, the underphosphorylated and less active form of topo I in H23 cells can be activated by CK2 treatment in vitro, consistent with a possible role for CK2 in regulating cellular sensitivity to camptothecin (6). Phosphorylation of serine 21 by PKC has been found to promote increased sensitivity of topo I to camptothecin (22), consistent with a previous study showing that PKC enhances the sensitivity of the enzyme to camptothecin (16). Taken together, these observations suggest that one or more topo I serine phosphorylating activities could have a general role in a variety of cancers to regulate topo I activity in vivo in ways that affect the cellular response to camptothecin-related drugs.…”
supporting
confidence: 89%
“…The previously-identified CK2-targeted site at serine 10, together with a PKC-targeted site at serine 21, and two cdk-1-targeted sites at serines 112 and 394, are preferentially phosphorylated in mitotic cells, suggesting a possible role for these sites during mitosis (22). Of these four sites, only the PKC-targeted site at serine 21 has been linked to increased topo I activity (22).…”
Section: Discussionmentioning
confidence: 98%
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“…Phosphorylation of the serine residues in DNA topoisomerase I was demonstrated by casein kinase II (Ser 10 ), protein kinase Cα (Ser 21 ), and Cdk1 (Ser 112 and Ser 394 ). Phosphorylation of serine 21 by protein kinase Cα, a protein kinase activated by IL-2, resulted in a two-fold increase in the activity of the enzyme and a stabilization of camptothecin-induced cleavable complexes [29] supporting the hypothesis that phosphorylation can activate DNA topoisomerase I at least modestly. Since protein kinase Cα, casein kinase II, and cyclin-dependent kinase are all activated by IL-2 [8], the increased activity of DNA topoisomerase I observed in HuT 78 cells activated by IL-2 may be due at least in part to phosphorylation of the enzyme by protein kinases that are activated by IL-2.…”
Section: Discussionmentioning
confidence: 96%
“…Dephosphorylation inhibits the activity of DNA topoisomerase I, and phosphorylation of both enzymes by casein kinase II or protein kinase Cα stimulates their activities [28]. Increased phosphorylation of DNA topoisomerase I was observed at four serines residues (10, 21, 112, and 394) in mitotic K562 cells [29]. Phosphorylation of the serine residues in DNA topoisomerase I was demonstrated by casein kinase II (Ser 10 ), protein kinase Cα (Ser 21 ), and Cdk1 (Ser 112 and Ser 394 ).…”
Section: Discussionmentioning
confidence: 99%