TRIM29 regulates the assembly of DNA repair proteins into damaged chromatin.

Yasushi Masuda,Chieri Tomomori-Sato,Shigetsugu Hatakeyama,Joan W Conaway,Ronald C Conaway,Shigeo Sato,Michael P Washburn,Anita Saraf,Hidehisa Takahashi,Laurence Florens

doi:10.1038/ncomms8299

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, DNA-PKcs 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.

Highlights

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
We found that Tripartite motif protein 29 (TRIM29) directly binds to MSH2, which is a key regulator of the mismatch repair (MMR) pathway[8], raising the possibility that TRIM29 regulates the MMR pathway (Fig. 3)
In this study, we showed that TRIM29 is a histone-binding protein involved in the incorporation of DNA repair proteins into chromatin (Fig. 8e)

Summary

Introduction

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. Our results suggest that TRIM29 functions as a scaffold protein to assemble DNA repair proteins into chromatin followed by efficient activation of DDR. Histone H2AX at Ser 139 is rapidly phosphorylated by ATM and DNA-PKcs in response to DSBs5. Following the induction of phosphorylated H2AX at Ser 139 (gH2AX), many regulators of the DNA repair pathway accumulate at DSB sites and activate the DSB repair pathway[6,7]. In addition to these sensor factors of DSBs, various proteins contribute to the DSB repair pathway. We propose that TRIM29 functions as a scaffold protein incorporating DNA repair proteins into chromatin and contributes to efficient activation of DNA damage signalling

Methods

Results

Conclusion