Poly(ADP-ribose) Reactivates Stalled DNA Topoisomerase I and Induces DNA Strand Break Resealing

Regulating the topological state of DNA is a vital function of the enzyme DNA topoisomerase I. However, when acting on damaged DNA, topoisomerase I may get trapped in a covalent complex with nicked DNA (stalled topoisomerase I), that, if unrepaired, may lead to genomic instability or cell death. Her...

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Veröffentlicht in:The Journal of biological chemistry 2004-02, Vol.279 (7), p.5244-5248
Hauptverfasser: Malanga, Maria, Althaus, Felix R.
Format: Artikel
Sprache:eng
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Zusammenfassung:Regulating the topological state of DNA is a vital function of the enzyme DNA topoisomerase I. However, when acting on damaged DNA, topoisomerase I may get trapped in a covalent complex with nicked DNA (stalled topoisomerase I), that, if unrepaired, may lead to genomic instability or cell death. Here we show that ADP-ribose polymers target specific domains of topoisomerase I and reprogram the enzyme to remove itself from cleaved DNA and close the resulting gap. Two members of the poly(ADP-ribose) polymerase family, PARP-1 and 2, act as poly(ADP-ribose) carriers to stalled topoisomerase I sites and induce efficient repair of enzyme-associated DNA strand breaks. Thus, by counteracting topoisomerase I-induced DNA damage, PARP-1 and PARP-2 act as positive regulators of genomic stability in eukaryotic cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C300437200