Recognition of platinum-DNA damage by Poly(ADP-ribose) polymerase-1

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Detail(s)

Original languageEnglish
Pages (from-to)6177-6183
Journal / PublicationBiochemistry
Volume49
Issue number29
Publication statusPublished - 27 Jul 2010
Externally publishedYes

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. © 2010 American Chemical Society.

Citation Format(s)

Recognition of platinum-DNA damage by Poly(ADP-ribose) polymerase-1. / Zhu, Guangyu; Chang, Paul; Lippard, Stephen J.

In: Biochemistry, Vol. 49, No. 29, 27.07.2010, p. 6177-6183.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal