Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aided by sensitive sequence profile searches we identify a novel conserved domain in the N-terminal regions of the SWI2/SNF2 proteins typified by HIP116 and Rad5p (hence HIP116, Rad5p N-terminal domain: HIRAN domain). We show that the HIRAN domain is found as a standalone protein in several bacteria and prophages, or fused to other catalytic domains, such as a nuclease of the restriction endonuclease fold and TDP1-like DNA phosphoesterases, in the eukaryotes. Based on a network of contextual connections in the form of domain architectures, conserved gene neighborhoods and functional interactions we predict that the HIRAN domain is likely to function as a DNA-binding domain that probably recognizes features associated with damaged DNA or stalled replication forks. It might thus act as a sensor to initiate a damaged DNA checkpoint and engage different DNA repair and chromatin remodeling or modifying activities to these sites. In evolutionary terms, the fusion of the HIRAN domain, and the functionally analogous RAD18 Zn-finger and the PARP-type Zn-finger to SWI2/SNF2 ATPases appears to have been a notable factor for recruiting these ATPases for chromatin modification and remodeling in the context of DNA repair.
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PMID:The HIRAN domain and recruitment of chromatin remodeling and repair activities to damaged DNA. 1662 93

Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists of two parts. In the first part ("Lessons"), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the "interfacial inhibition" by which topoisomerase-targeted drugs act as topoisomerase poisons, and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisomerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein-DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmet need to develop inhibitors for type IA enzymes.
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PMID:Drugging topoisomerases: lessons and challenges. 2325 82