TRIM29 regulates the assembly of DNA repair proteins into damaged chromatin

Abstract

Although DNA double-strand break (DSB) repair is mediated by numerous proteins accumulated at DSB sites, how DNA repair proteins are assembled into damaged chromatin has not been fully elucidated. Here we show that a member of the tripartite motif protein family, TRIM29, is a histone-binding protein responsible for DNA damage response (DDR). We found that TRIM29 interacts with BRCA1-associated surveillance complex, cohesion, DNAPKcs and components of TIP60 complex. The dynamics of the TRIM29-containing complex on H2AX nucleosomes is coordinated by a cross-talk between histone modifications. TRIM29 binds to modified histone H3 and H4 tails in the context of nucleosomes. Furthermore, chromatin binding of TRIM29 is required for the phosphorylation of H2AX and cell viability in response to ionizing radiation. Our results suggest that TRIM29 functions as a scaffold protein to assemble DNA repair proteins into chromatin followed by efficient activation of DDR.

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

“…These findings suggest that the ATDC-RNF8 interaction may have a more global effect on RNF8 nuclear dynamics, which occurs outside of the DNA repair foci but which is nonetheless important for efficient DNA repair (Table 1). These results are also consistent with a recent study identifying ATDC/TRIM29 as a nuclear DDR participant that binds to the chromatin following DNA damage (18).…”

“…Although the exact means by which the ATDC-RNF8 interaction impacts the function of RNF8 is incompletely understood, ATDC is known to bind the acetyltransferase Tip60, which is involved in chromatin remodeling and promotes RNF8 ubiquitin ligase activity and DNA repair (12,30). Furthermore, our mass spectrometry screen also identified a putative interaction between ATDC and RuvBL2 (Tip48), another member of the p400/NuA4 complex that modulates RNF8 activity (Table 1) (18). We therefore hypothesize that ATDC may promote RNF8 activity, perhaps by physically binding to and coordinating the activity of the chromatin-remodeling complexes necessary for RNF8 to promote efficient DNA DSB repair.…”

“…These results establish the ATDC-RNF8 interaction as a key mechanism of ATDC-induced resistance to IR. ATDC has previously been described as a driver of resistance to DNA damage by UV and ionizing radiation that binds to chromatin, but the exact means by which it promotes resistance to DNA damage was unclear (18,25,26). Like ATDC, RNF8 is activated in an ATM-dependent manner and participates in DDR by facilitating DNA DSB processing through ubiquitination of histones and DNA repair factors promoting the assembly of DNA repair complexes at sites of DNA DSB (3,4).…”

“…Other groups have reported that in certain cell lines, it is predominately present in the nucleus (18). RNF8 has been shown to have nuclear localization and to localize to sites of DNA damage after irradiation (4).…”

“…Phosphorylation of ATDC is required to mediate resistance to IR (17). ATDC has also been shown to bind to chromatin and activate the DDR following DSB formation (18). The mechanism(s) downstream of ATDC that mediate radioresistance, however, are not known.…”