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Please use this identifier to cite or link to this item: http://hdl.handle.net/10400.18/290

Title: Cost/Benefit of Mutation Induction under PARP1 Deficiency: From Genomic Instability to Therapy
Authors: Louro, Henriqueta
Silva, Maria João
Keywords: DNA repair
Mutation
PARP1
Transgenic mouse
Genotoxicidade Ambiental
Issue Date: 2011
Publisher: Nova Science Publishers, Inc.
Series/Report no.: Advances in Genetic Research;4
Abstract: Mutation is a possible consequence of DNA damage and it is the most prominent event of the carcinogenic process. Spontaneous mutations originate from endogenous metabolic processes, such as inaccurate DNA replication or repair, whereas induced mutations arise from exposure to exogenous agents. Once DNA damage occurs, a complex network of repair functions is triggered to protect cells against the deleterious consequences of mutations and in order to maintain genomic stability. Among the several DNA repair pathways available in eukaryotic cells, base excision repair (BER) is required to repair non-bulky DNA adducts such as oxidized bases. Poly (ADP-ribose) polymerase-1 (PARP1) is a ubiquitous protein in mammalian cells, with a relevant role in BER and participating also in other complex biochemical processes including double strand break repair, chromatin remodelling and cell death. Hence, defective PARP1 activity would be expected to influence the number or type of gene and/or chromosome mutations resultant from exposure to genotoxic agents and, eventually, to be implicated in cancer. Recently, we generated a Parp1-/- lacZ transgenic mouse model to investigate the effect of PARP1 deficiency in vivo on the mutagenic and clastogenic responses to carcinogens. In this chapter, we present data showing the occurrence of a higher spontaneous genomic instability and a modified mutagenic response to genotoxic insults in Parp1-deficient mice. Particularly, the higher level of deletion mutations in the germ line of those mice might constitute an added risk for hereditary diseases. Inversely, it might provide genetic diversity, representing an advantage for survival. Interestingly, although we found that PARP1 inactivation causes some genomic instability in vivo, cancer propensity was not observed either in this mouse line or in two other different Parp1-deficient mouse models. Even though, defects in DNA damage responses that are not directly responsible for a disease can be important and exploited to be used for the benefit of health. This has been the case of molecules acting as PARP inhibitors, which have been developed to enhance the effectiveness of anticancer drugs or even to function as chemotherapeutic agents per se. The rational for their therapeutic application is based, precisely, on the increase of mutations in tumor cells upon PARP1 abrogation, triggering cell death. However, considering the present knowledge about the impact of PARP1 deficiency in mutation accumulation and the uncertainties about its association with somatic or hereditary diseases, the cost/benefit of the clinical use of PARP inhibitors in humans should be carefully evaluated.
Peer Reviewed: no
URI: http://hdl.handle.net/10400.18/290
ISBN: 978-1-61728-764-0
ISSN: 2159-1563
Publisher version: https://www.novapublishers.com/catalog/product_info.php?products_id=15786
Appears in Collections:DGH - Capítulos (ou partes) de livros

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