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Int. J. Mol. Sci. 2017, 18(4), 788; doi:10.3390/ijms18040788

Microvesicles Contribute to the Bystander Effect of DNA Damage

1
Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada
2
Father Sean O’Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada
3
The Hamilton Center for Kidney Research, St. Joseph’s Hospital, Hamilton, ON L8N 4A6, Canada
4
The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital, Longgang District, Shenzhen 518116, Guangdong, China
5
Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Guillermo T. Sáez
Received: 13 February 2017 / Revised: 5 April 2017 / Accepted: 5 April 2017 / Published: 7 April 2017
(This article belongs to the Special Issue DNA Injury and Repair Systems)
View Full-Text   |   Download PDF [9602 KB, uploaded 7 April 2017]   |  

Abstract

Genotoxic treatments elicit DNA damage response (DDR) not only in cells that are directly exposed but also in cells that are not in the field of treatment (bystander cells), a phenomenon that is commonly referred to as the bystander effect (BE). However, mechanisms underlying the BE remain elusive. We report here that etoposide and ultraviolet (UV) exposure stimulate the production of microvesicles (MVs) in DU145 prostate cancer cells. MVs isolated from UV-treated DU145 and A431 epidermoid carcinoma cells as well as etoposide-treated DU145 cells induced phosphorylation of ataxia-telangiectasia mutated (ATM) at serine 1981 (indicative of ATM activation) and phosphorylation of histone H2AX at serine 139 (γH2AX) in naïve DU145 cells. Importantly, neutralization of MVs derived from UV-treated cells with annexin V significantly reduced the MV-associated BE activities. Etoposide and UV are known to induce DDR primarily through the ATM and ATM- and Rad3-related (ATR) pathways, respectively. In this regard, MV is likely a common source for the DNA damage-induced bystander effect. However, pre-treatment of DU145 naïve cells with an ATM (KU55933) inhibitor does not affect the BE elicited by MVs isolated from etoposide-treated cells, indicating that the BE is induced upstream of ATM actions. Taken together, we provide evidence supporting that MVs are a source of the DNA damage-induced bystander effect. View Full-Text
Keywords: DNA damage response; microvesicles; γH2AX; ATM; ATR DNA damage response; microvesicles; γH2AX; ATM; ATR
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MDPI and ACS Style

Lin, X.; Wei, F.; Major, P.; Al-Nedawi, K.; Al Saleh, H.A.; Tang, D. Microvesicles Contribute to the Bystander Effect of DNA Damage. Int. J. Mol. Sci. 2017, 18, 788.

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