ACRC/GCNA is an essential protease for the repair of DNA-protein crosslinks during vertebrate development

Abstract

SummaryDNA-protein crosslinks (DPCs) are frequent DNA lesions associated with cancer, neurodegeneration and premature aging. These bulky lesions are an obstacle to all DNA transactions, but the mechanisms of DPC repair (DPCR) at the organism level are largely unknown. Because proteases play a central role in DPCR, we investigate the function of the putative protease ACRC/GCNA (ACidic Repeat Containing/Germ Cell Nuclear Antigen) which has recently been linked to DPCR, in a zebrafish model. Using a newly created fish line with a mutation in the protease core, we show for the first time that the proteolytic function of Acrc is critical for DPCR during early vertebrate development and that Acrc deficiency leads to DPC accumulation and embryonic death. We also show that Sprt domain rather than IDR domain of Acrc is essential and that Sprtn protease cannot compensate for the absence of Acrc. We identified histone H3-DPC as a novel Acrc substrate.