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Cells 2019, 8(2), 116; https://doi.org/10.3390/cells8020116

Diastereomeric Recognition of 5’,8-cyclo-2’-Deoxyadenosine Lesions by Human Poly(ADP-ribose) Polymerase 1 in a Biomimetic Model

1
Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, 40129 Bologna, Italy
2
Dipartimento di Biologia, Università di Napoli “Federico II”, 80138 Napoli, Italy
3
Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA
4
Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA
5
Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA
6
Institute of Nanoscience and Nanotechnology, NCSR Demokritos Agia Paraskevi, 15310 Athens, Greece
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Received: 21 December 2018 / Revised: 20 January 2019 / Accepted: 1 February 2019 / Published: 2 February 2019
(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease)
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Abstract

5’,8-Cyclo-2’-deoxyadenosine (cdA), in the 5’R and 5’Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by the nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the two diastereomeric cdA lesions could induce specific PARP1 binding. Here, we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions of 5’S-cdA and 5’R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism, fluorescence spectroscopy, immunoblotting analysis, and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1 were characterized. Remarkably, PARP1 exhibits different affinities in binding to a double strand (ds) oligonucleotide, which incorporates cdA lesions in R and S diastereomeric form. In particular, PARP1 proved to bind oligonucleotides, including a 5’S-cdA, with a higher affinity constant for the 5’S lesion in a model of ds DNA than 5’R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion. View Full-Text
Keywords: human poly(ADP-ribose) polymerase 1 (PARP1); PARP-DNA complex; DNA-protein binding; DNA repair; 5’,8-Cyclopurine-2’-deoxynucleoside; DNA damage; DNA repair efficiency human poly(ADP-ribose) polymerase 1 (PARP1); PARP-DNA complex; DNA-protein binding; DNA repair; 5’,8-Cyclopurine-2’-deoxynucleoside; DNA damage; DNA repair efficiency
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Masi, A.; Sabbia, A.; Ferreri, C.; Manoli, F.; Lai, Y.; Laverde, E.; Liu, Y.; Krokidis, M.G.; Chatgilialoglu, C.; Faraone Mennella, M.R. Diastereomeric Recognition of 5’,8-cyclo-2’-Deoxyadenosine Lesions by Human Poly(ADP-ribose) Polymerase 1 in a Biomimetic Model. Cells 2019, 8, 116.

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