Structural basis for EPC1-mediated recruitment of MBTD1 into the NuA4/TIP60 acetyltransferase complex

MBTD1 has recently been identified to join the NuA4/TIP60 acetyltransferase complex to regulate gene expression and DNA repair. MBTD1 competes with 53BP1 for recognition of the H4K20me mark, while MBTD1-associated TIP60 carries out the acetylation of H2AK15 and thereby blocks the ubiquitylation-dependent association of 53BP1 to the sites of DNA double strand breaks. Interestingly, the non-catalytic subunit EPC1 has been shown to enlist MBTD1 into the dynamic NuA4/TIP60 acetyltransferase complex, but the detailed molecular mechanism remains unexplored. Here, we present the crystal structure of the MBTD1-EPC1 complex that sheds light on the molecular mechanism by which MBTD1 recognizes EPC1. Mutational analysis coupled with functional evaluations in human cell lines validate the physiological significance of the key residues involved in the MBTD1-EPC1 association. Overall, our study provides a structural framework for understanding the mechanism by which MBTD1 recruits the NuA4/TIP60 acetyltransferase complex to influence transcription and DNA repair pathway choice.