Induction of DNA damage and erroneous repair can explain genomic instability caused by endosulfan

Sebastian, Robin and Raghavan, Sathees C (2016) Induction of DNA damage and erroneous repair can explain genomic instability caused by endosulfan. In: CARCINOGENESIS, 37 (10). pp. 929-940.

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Abstract

In this study, the authors report the molecular mechanism for genomic instability induced by an organochlorine pesticide, Endosulfan. In both human cells and rodent tissues, Endosulfan induce DNA breaks, perturbs damage response leading to compromised repair with reduced fidelity.Endosulfan (ES) is an organochlorine pesticide, speculated to be associated with chromosomal abnormalities and diseases in humans. However, very little is known about the mechanism of its genotoxicity. Using in vivo, ex vivo and in vitro model systems, we show that exposure to ES induces reactive oxygen species (ROS) in a concentration and time-dependent manner. The generation of ROS results in DNA double-strand breaks either directly or in a replication-dependent manner, both in mice and human cells. Importantly, ES-induced DNA damage evokes DNA damage response, resulting in elevated levels of classical non-homologous DNA endjoining (NHEJ), the predominant double-strand break repair pathway in higher eukaryotes. Sequence analyses of NHEJ junctions revealed that ES treatment results in extensive processing of broken DNA, culminating in increased and long junctional deletions, thereby favoring erroneous repair. We also find that exposure to ES leads to significant increase in microhomology-mediated end joining (MMEJ), a LIGASE III-dependent alternative repair pathway. Therefore, we demonstrate that ES induces DNA damage and genomic instability, alters DNA damage response thereby promoting erroneous DNA repair.

Item Type:	Journal Article
Publication:	CARCINOGENESIS
Additional Information:	Copy right for this article belongs to the OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	03 Dec 2016 10:13
Last Modified:	03 Dec 2016 10:13
URI:	http://eprints.iisc.ac.in/id/eprint/55415

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