CC3/TIP30 affects DNA damage repair

Sylvia Fong,Frank King,Emma Shtivelman

doi:10.1186/1471-2121-11-23

Abstract

BackgroundThe pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress.ResultsWe found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult.ConclusionsManipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.

Highlights

The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport
We have examined if delays in DNA damage repair observed in U373cc3 cells have an effect on cell viability or proliferation
We have chosen to examine the possible consequences of forced expression of CC3 on DNA damage repair in a glioblastoma cell line lacking endogenous CC3, because introduction of CC3 did not affect its proliferation rate or sensitivity to death signals, unlike negative effects reported in many other tumor cell lines stably transfected with CC3 ([2])

Summary

Introduction

The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. Forced expression of CC3 in vSCLC [1], mouse melanoma, breast carcinoma [10], hepatocellular carcinoma [6] and gastric carcinoma cell lines [5] inhibits metastatic behavior in vitro and/or metastasis in vivo. One study on the role of TIP30 in metastasis reported that TIP30 expression enhances growth and metastatic behavior of prostate carcinoma cells in vitro [14], but majority of published results support the hypothesis that CC3/TIP30 suppresses tumor development and metastasis. Expression of CC3 in CC3-negative tumor cells has an inhibitory effect on the ability of these cells to produce angiogenic factors in vitro [2], consistent with the conclusion that down regulation of CC3 contrib-

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