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Recognition of Platinum−DNA Damage by Poly(ADP-ribose) Polymerase-1

Author(s)
Zhu, Guangyu; Chang, Paul; Lippard, Stephen J.
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Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) was recently identified as a platinum−DNA damage response protein. To investigate the properties of binding of PARP-1 to different platinum−DNA adducts in greater detail, biotinylated DNA probes containing a site-specific cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link or a cisplatin 5′-GC/5′-GC interstrand cross-link (ICL) were utilized in binding assays with cell-free extracts (CFEs) in vitro. The activated state of PARP-1 was generated by treatment of cells with a DNA-damaging agent or by addition of NAD+ to CFEs. PARP-1 binds with a higher affinity to cisplatin-damaged DNA than to undamaged DNA, and the amount of protein that binds to the most common cisplatin−DNA cross-link, 1,2-d(GpG), is greater than the amount that binds to other types of cisplatin−DNA cross-links. Both DNA damage-activated PARP-1 and unactivated PARP-1 bind to cisplatin-damaged DNA, and both automodified PARP-1 and cleaved PARP-1 bind to cisplatin−DNA lesions. The role of poly(ADP-ribose) (pADPr) in mediating binding of PARP-1 to platinum damage was further investigated. The extent of binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link decreases upon automodification, and overactivated PARP-1 loses its affinity for the cross-link. Elimination of pADPr facilitates binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link. PARP-1 also binds to DNA damaged by other platinum compounds, including oxaliplatin and pyriplatin, indicating protein affinity for the damage in an adduct-specific manner rather than recognition of distorted DNA. Our results reveal the unique binding properties for binding of PARP-1 to platinum−DNA damage, providing insights into, and a better understanding of, the cellular response to platinum-based anticancer drugs.
Date issued
2010-06
URI
http://hdl.handle.net/1721.1/64758
Department
Massachusetts Institute of Technology. Department of Chemistry; Koch Institute for Integrative Cancer Research at MIT
Journal
Biochemistry
Publisher
American Chemical Society
Citation
Zhu, Guangyu, Paul Chang, and Stephen J. Lippard. “Recognition of Platinum−DNA Damage by Poly(ADP-ribose) Polymerase-1.” Biochemistry 49.29 (2010) : 6177-6183.
Version: Author's final manuscript
ISSN
0006-2960
1520-4995

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