Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability

Abstract

Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. We investigated the mechanism of this nontargeted effect in human mammary epithelial cells (HMEC) exposed to low doses of radiation. We identified a centrosome-associated expression signature in irradiated HMEC and show here that centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy, and aneuploidy. Clonal analysis of genomic instability showed a threshold of >10 cGy. Treatment with transforming growth factor B1 (TGFB), which is implicated in regulation of genomic stability and is activated by radiation, reduced both the centrosome expression signature and centrosome aberrations in irradiated HMEC. Furthermore, TGFB inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFB selectively deleted unstable cells via p53-dependent apoptosis. Together, these studies show that radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that this can be opposed by radiation-induced TGFB signaling.

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

“…The challenging doses of X-irradiation were in the low dose range to evidence the influence of SMOX activity, mainly related to proliferation and survival. In fact, doses <10 cGy do not deliver any mutation and genomic instability (32), thus are out of the scope of this study. In NB cell line, SMOX delivered an effect not in agreement with the LNT theory, causing hypersensitivity at lower dose and adaptive response at the higher dose of 10 cGy.…”

TGF- Biology in Mammary Development and Breast Cancer

“…Although loss of growth regulation is thought to be the primary benefit of overcoming TGF-b control, recent studies show significantly increased centrosome instability, tetraploidy, and aneuploidy (e.g., markers of genomic instability) when TGF-b signaling or production is restricted in normal human and mouse mammary epithelia (Maxwell et al 2008). Addition of TGF-b suppressed all three measures of genomic instability while increasing apoptosis, suggesting that aberrant cells are selectively deleted via ATM kinase-sensitive, p53-dependent apoptosis.…”

A Putatively Functional Haplotype in the Gene Encoding Transforming Growth Factor Beta-1 as a Potential Biomarker for Radiosensitivity

“…Transforming growth factor-b1 promotes apoptosis in activated or heavily damaged lymphocytes (11,12). Furthermore, activity of TGF-b was shown to be involved in DNA repair upon irradiation (13,14).…”