Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells

Abstract

Background: Long interspersed nuclear elements (LINEs), Alu and endogenous retroviruses (ERVs) make up some 45% of human DNA. LINIE-I also called L1, is the most common family of non-LTR retrotransposons in the human genome and comprises about 17% of the genome. LI elements require the integration into chromosomal target sites using LI-encoded endonuclease which creates staggering DNA breaks allowing the newly transposed LI copies to integrate into the genome. LI expression and retrotransposition in cancer cells might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome instability. There is however little evidence on the mechanism of LI-induced genetic instability and its impact on cancer cell growth and proliferation. Results: We report that LI has genome-destabilizing effects indicated by an accumulation of γ-H2AX foci, an early response to DNA strand breaks, in association with an abnormal cell cycle progression through a G2/M accumulation and an induction of apoptosis in breast cancer cells. In addition, we found that adjuvant LI activation may lead to supra-additive killing when combined with radiation by enhancing the radiation lethality through induction of apoptosis that we have detected through Bax activation. Conclusion: LI retrotransposition is sensed as a DNA damaging event through the creation DNA breaks involving LI-encoded endonuclease. The apparent synergistic interaction between LI activation and radiation can further be utilized for targeted induction of cancer cell death. Thus, the role of retrotransoposons in general, and of LI in particular, in DNA damage and repair assumes larger significance both for the understanding of mutagenicity and, potentially, for the control of cell proliferation and apoptosis. © 2006 Belgnaoui et al; licensee BioMed Central Ltd.