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Double-stranded DNA binding domain of poly(ADP-ribose) polymerase-1 and molecular insight into the regulation of its activity.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Mar 04; Vol. 286 (9), pp. 7149-60. Date of Electronic Publication: 2010 Dec 23. - Publication Year :
- 2011
-
Abstract
- Poly(ADP-ribose) polymerase-1 (PARP-1) modifies various proteins, including itself, with ADP-ribose polymers (automodification). Polymer synthesis is triggered by binding of its zinc finger 1 (Zn1) and 2 (Zn2) to DNA breaks and is followed by inactivation through automodification. The multiple functional domains of PARP-1 appear to regulate activation and automodification-mediated inactivation of PARP-1. However, the roles of these domains in activation-inactivation processes are not well understood. Our results suggest that Zn1, Zn2, and a domain identified in this study, the double-stranded DNA binding (DsDB) domain, are involved in DNA break-dependent activation of PARP-1. We found that binding of the DsDB domain to double-stranded DNA and DNA break recognition by Zn1 and Zn2, whose actual binding targets are likely to be single-stranded DNA, lead to the activation of PARP-1. In turn, the displacement of single- and double-stranded DNA from Zn2 and the DsDB domain caused by ADP-ribose polymer synthesis results in the dissociation of PARP-1 from DNA breaks and thus its inactivation. We also found that the WGR domain is one of the domains involved in the RNA-dependent activation of PARP-1. Furthermore, because zinc finger 3 (Zn3) has the ability to bind to single-stranded RNA, it may have an indirect role in RNA-dependent activation. PARP-1 functional domains, which are involved in oligonucleic acid binding, therefore coordinately regulate PARP-1 activity depending on the status of the neighboring oligonucleic acids. Based on these results, we proposed a model for the regulation of PARP-1 activity.
- Subjects :
- Adenosine Diphosphate Ribose metabolism
Binding Sites physiology
DNA Breaks, Double-Stranded
Humans
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Poly (ADP-Ribose) Polymerase-1
Protein Structure, Tertiary
RNA metabolism
Structure-Activity Relationship
Zinc Fingers physiology
DNA metabolism
DNA Damage physiology
DNA, Single-Stranded metabolism
Models, Chemical
Poly(ADP-ribose) Polymerases chemistry
Poly(ADP-ribose) Polymerases genetics
Poly(ADP-ribose) Polymerases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21183686
- Full Text :
- https://doi.org/10.1074/jbc.M110.175190