The ATDC (TRIM29) Protein Binds p53 and Antagonizes p53-Mediated Functions

Abstract

The ataxia telangiectasia group D-complementing (ATDC) gene product, also known as TRIM29, is a member of the tripartite motif (TRIM) protein family. ATDC has been proposed to form homo-or heterodimers and to bind nucleic acids. In cell cultures, ATDC expression leads to rapid growth and resistance to ionizing radiation (IR), whereas silencing of ATDC expression decreases growth rates and increases sensitivity to IR. Although ATDC is overexpressed in many human cancers, the biological significance of ATDC overexpression remains obscure. We report here that ATDC increases cell proliferation via inhibition of p53 nuclear activities. ATDC represses the expression of p53-regulated genes, including p21 and NOXA. Mechanistically, ATDC binds p53, and this interaction is potentially fine-tuned by posttranslational acetylation of lysine 116 on ATDC. The association of p53 and ATDC results in p53 sequestration outside of the nucleus. Together, these results provide novel mechanistic insights into the function of ATDC and offer an explanation for how ATDC promotes cancer cell proliferation.Ataxia telangiectasia (AT) is an autosomal-recessive, complex, multisystem disorder (4, 33). One of the hallmarks for cells derived from AT patients is their unusual sensitivity to ionizing radiation (IR) and their failure to delay the cell cycle in S phase, termed radioresistant DNA synthesis. In addition, AT cells contain atypical cytoskeletal organization. An early attempt to complement the defect in an AT cell line (AT5BIVA) by transfection with a human cosmid library and selection by ␥IR resulted in the isolation of an AT cell line (1B3) that was partially resistant to IR (22). Subsequent isolation of the human DNA in the region of the integrated cosmid sequences in 1B3 cells resulted in the cloning of the ataxia telangiectasia group D-complementing (ATDC) gene (23).The ATDC gene is located at chromosome 11q23, where it is frequently associated with many different kinds of cancers. Analysis of the ATDC gene product revealed that it is a member of the tripartite motif (TRIM) protein family (also known as the RBCC family). This protein family is characterized by three zinc-binding domains, a RING, a B-box type 1, and a B-box type 2, followed by a coiled-coil region (5,29,42,43,47). Some TRIM proteins homo-multimerize through their coilcoil region, and the integrity of the TRIM motif is required for proper subcellular localization of TRIM proteins (43). Recently, it was discovered that one of the TRIM proteins is a component of the repressor binding site (RBS) binding complex found in EC and ES cells and functions in restricting retroviral replication (60).The ATDC protein has been shown to interact with a protein kinase C substrate and inhibitor, although the significance of this interaction is not exactly clear (6). Although early studies indicate that ATDC can complement the IR sensitivity of AT fibroblasts, later analysis reveals that ATDC does not affect radioresistant DNA synthesis and is most likely not mutated in any AT patient...

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase

“…These results implicate RNF8 as an additional binding partner that influences DNA repair and resistance to damage. Together these findings suggest ATDC as a multifunctional scaffold protein that undergoes covalent modifications (phosphorylation, acetylation) following cellular insults and subsequently binds to multiple proteins in the cytoplasm and nucleus to coordinate cellular survival and DNA repair (10,17,25).…”

“…Indeed, ATDC seems to function as a direct protein link between proteins involved in DNA damage sensing (ATM-p38-MK2) and cell cycle regulation (DVL2, p53) (10,17,25). These results implicate RNF8 as an additional binding partner that influences DNA repair and resistance to damage.…”

“…Shuttling-ATDC has previously been reported to localize predominantly to the cytoplasm and cytoskeleton of cells (10). Other groups have reported that in certain cell lines, it is predominately present in the nucleus (18).…”

“…Others have demonstrated that knockdown of ATDC sensitizes cells to UV irradiation (26). ATDC has also been reported to interact with p53 through its N terminus and to inhibit p53 nuclear activity (10). To confirm the importance of ATDC for radioresistance, we next investigated the survival rate of HEK 293 cells with stable expression of full-length ATDC, ATDC⌬220(⌬N), or ATDC⌬C (Fig.…”

“…In pancreatic cancer cells, ATDC has been shown to interact with DVL-2 through its coiled-coil domain, leading to the promotion of cell proliferation and invasion (17). ATDC also binds to p53, influencing cell cycle progression (10,17). We have recently demonstrated that ATDC is a downstream phosphorylation target of ATM and MAPKAPK2 (MAPKactivated protein kinase 2) following exposure to IR.…”