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E2F1-mediated DNA damage is implicated in 8-Cl-adenosine-induced chromosome missegregation and apoptosis in human

Yu-Ying Han¹, Zhe Zhou, Ji-Xiang Cao

¹Department of Biochemistry and Molecular Biology, Capital Medical University, You An Men 8, Beijing, 100069, People's Republic of China.

Molecular and Cellular Biochemistry

|September 17, 2013

Abstract:

Although E2F1-mediated DNA double-stranded breaks (DSBs) and tetraploid have been extensively studied, the role of E2F1 in mitotic catastrophe is still unknown. We have previously shown that 8-chloro-adenosine (8-Cl-Ado) induces DNA DSBs and aberrant mitosis in human lung cancer cells, followed by delayed apoptosis. Here, we demonstrate that E2F1-mediated DNA damage is implicated in 8-Cl-Ado-induced chromosome missegregation and apoptosis in lung cancer H1299 cells. We showed that E2F1 was accumulated upon 8-Cl-Ado-induced DNA DSBs. Induction of E2F1 by 8-Cl-Ado caused DNA damage in cycling cells including M cells. In contrast, silencing of E2F1 expression decreased 8-Cl-Ado-induced DNA DSBs, particularly eliminated E2F1-mediated mitotic DNA damage. Over-expression of E2F1 and/or 8-Cl-Ado exposure resulted in aberrant mitotic spindles and chromosome segregation errors. Furthermore, over-expression of E2F1 expression enhanced 8-Cl-Ado-induced apoptosis. Together, our data indicate that E2F1-mediated DNA damage, in particular mitotic DNA damage, is an important fraction of 8-Cl-Ado-induced DNA damage, which is implicated in 8-Cl-Ado-induced mitotic catastrophe and delayed apoptosis. Induction of E2F1 by 8-Cl-Ado may contribute at least partly to the drug-inhibited proliferation of cancer cells.

Insights

8-chloro-adenosine (8-Cl-Ado) induces DNA damage and apoptosis in lung cancer cells by accumulating E2F1. This E2F1-mediated damage, especially during mitosis, contributes to cancer cell death and proliferation inhibition.

Area of Science:

Molecular Biology
Cancer Research
Cell Biology

Background:

E2F1's role in DNA double-stranded breaks (DSBs) and tetraploidy is known, but its function in mitotic catastrophe remains unclear.
Previous research demonstrated that 8-chloro-adenosine (8-Cl-Ado) induces DSBs and aberrant mitosis in human lung cancer cells, leading to delayed apoptosis.

Purpose of the Study:

To investigate the role of E2F1 in 8-chloro-adenosine (8-Cl-Ado)-induced mitotic catastrophe and apoptosis in human lung cancer cells.
To elucidate the mechanism by which E2F1 contributes to DNA damage and cell death following 8-Cl-Ado treatment.

Main Methods:

Utilized human lung cancer H1299 cells.
Analyzed E2F1 accumulation and DNA damage in response to 8-Cl-Ado.
Investigated the effects of E2F1 silencing and overexpression on 8-Cl-Ado-induced DNA damage, mitotic aberrations, and apoptosis.
Observed mitotic spindle morphology and chromosome segregation.

Main Results:

8-Cl-Ado treatment led to E2F1 accumulation, which in turn caused DNA damage, particularly in M-phase cells.
Silencing E2F1 reduced 8-Cl-Ado-induced DNA DSBs and mitigated E2F1-mediated mitotic DNA damage.
Overexpression of E2F1 enhanced 8-Cl-Ado-induced apoptosis and resulted in aberrant mitotic spindles and chromosome segregation errors.
8-Cl-Ado exposure, with or without E2F1 overexpression, caused chromosome missegregation.

Conclusions:

E2F1-mediated DNA damage, especially mitotic DNA damage, is a significant component of 8-Cl-Ado-induced cellular damage.
E2F1 plays a crucial role in 8-Cl-Ado-induced mitotic catastrophe and delayed apoptosis in lung cancer cells.
The induction of E2F1 by 8-Cl-Ado may contribute to the drug's ability to inhibit cancer cell proliferation.

Read full analysis

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