Role of the translationally controlled tumor protein in DNA damage sensing and repair

Abstract

The translationally controlled tumor protein (TCTP) is essential for survival by mechanisms that as yet are incompletely defined. Here we describe an important role of TCTP in response to DNA damage. Upon exposure of normal human cells to low-dose γ rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on ataxia-telangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase and was associated with protective effects against DNA damage. In chromatin of irradiated cells, coimmunoprecipitation experiments showed that TCTP forms a complex with ATM and γH2A.X, in agreement with its distinct localization with the foci of the DNA damage-marker proteins γH2A.X, 53BP1, and P-ATM. In cells lacking TCTP, repair of chromosomal damage induced by γ rays was compromised significantly. TCTP also was shown to interact with p53 and the DNA-binding subunits, Ku70 and Ku80, of DNA-dependent protein kinase. TCTP knockdown led to decreased levels of Ku70 and Ku80 in nuclei of irradiated cells and attenuated their DNA-binding activity. It also attenuated the radiation-induced G 1 delay but prolonged the G 2 delay. TCTP therefore may play a critical role in maintaining genomic integrity in response to DNA-damaging agents.low dose ionizing radiation | adaptive responses | DNA repair | cell cycle checkpoints | genomic stability

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

“…These results suggest that dTCTP can interlink HR and NHEJ in vivo. This idea is also consistent with a model recently proposed by Zhang et al 29 that hTCTP interlinks the HR and NHEJ pathways. In this model, hTCTP promotes Ku70/80 complex translocation for NHEJ repair and forms a complex with ATM for HR repair, although its function in HR pathway has not been clearly defined.…”

“…Indeed, both direct interaction and subcellular colocalization between them support this notion. Moreover, our genetic data and biochemical assays using dATM and its substrate (H2Av) illustrate that dTCTP directly facilitates dATM kinase activity by enhancing binding affinity of dATM to its substrate, providing a molecular basis for the relationship between TCTP and ATM that has not been studied before 29 . It is interesting to note that dATM is required for the formation of dTCTP foci but not vice versa.…”

“…Recently, it has been reported that hTCTP in irradiated fibroblast participates in DSB repair through Ku translocation and colocalization with ATM. However, the nature of hTCTP interaction with ATM and its physiological significance in animals remains unknown 29 .…”

“…In our search for new functions of dTCTP, we have found that dATM is a direct binding partner for dTCTP as described in this work. Interestingly, a recent study has suggested that human TCTP (hTCTP) plays a role for DNA damage control in fibroblast 29 . hTCTP is proposed as a target of ATM (ataxia telangiectasiamutated) kinase because hTCTP is upregulated by IR and this upregulation is suppressed by ATM depletion.…”

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…TCTP, genotoxic stress and genome stability. The participation of TCTP in the sensing and repair of DNA damage was first demonstrated by Zhang and colleagues in 2012 (Zhang et al 2012). This involved the up-regulation of TCTP after γ-irradiation of cells, its complex formation with the ataxia-telangiectasia mutated (ATM) kinase and with the histone γH2A.X and colocalisation with other DNA-damage marker proteins.…”