ACRC/GCNA is an essential protease that repairs DNA–protein crosslinks during vertebrate development

Otten, Cecile; Kutnjak, Marin; Supina-Pavić, Christine; Pranjić, Marija; Antičević, Ivan; Medved, Vanna; Popović, Marta (2026) ACRC/GCNA is an essential protease that repairs DNA–protein crosslinks during vertebrate development. Nucleic Acids Research, 54 (7). ISSN 0305-1048

PDF - Published Version - article Available under License Creative Commons Attribution. Download (3MB)

Abstract

DNA-protein crosslinks (DPCs) are toxic DNA lesions that block all DNA transactions including replication and transcription, and the consequences of impaired DNA-protein crosslink repair (DPCR) are severe. At the cellular level, impaired DPCR leads to the formation of double strand breaks, genomic instability, and cell death, while at the organismal level, it is associated with cancer, aging, and neurodegeneration. Despite its importance, the mechanisms of DPCR at the organismal level are largely unknown. Proteases play a central role in DPCR, as they remove proteinaceous part of the DPCs, while the peptide remnant crosslinked to DNA is subsequently removed by other repair factors. We characterized the role of putative protease ACRC/GCNA (ACidic Repeat Containing/Germ Cell Nuclear Antigen) in DPCR at the organismal level. For this purpose, we have created new animal models with CRISPR/Cas system: two zebrafish lines with inactive Acrc. We were able to overcome the early embryonic lethality caused by Acrc inactivation by injecting Acrc-WT messenger RNA and have created a viable animal model to study the role of Acrc in adult tissues. We identified histone H3, topoisomerases 1 and 2, Dnmt1, Parp1, Polr3a, and Mcm2 as putative DPC substrates of Acrc. We have shown that Acrc is essential for vertebrate development, and that the mechanism behind it is DPC removal.

Item Type:	Article
Uncontrolled Keywords:	DNA repair; DNA-protein crosslinks (DPCs); ACRC/GCNA protease; zebrafish; SPRTN; topoisomerases; Parp1; development
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division for Marine and Enviromental Research
Projects:	Project title Project leader Project code Project type Razumijevanje popravka unakrsnog vezanja DNA-Protein in vivo koristeći zebricu kao istraživački model-DNAPRO Marta Popović UIP-2017-05-5258 HRZZ Strukturna karakterizacija faktora uključenih u popravak unakrsnog vezanja DNA-protein- Marta Popović IPS-2020-01-4225 HRZZ STIM-REI-STIM-REI Vlasta Bonačić-Koutecky; Tvrtko Smital; Sandi Orlić; Ante Bilušić; Mile Dželalija; Damir Kovačić; Darko Koračin; Željka Sanader Maršić KK.01.1.1.01.0003 EK Popravak križnih veza topoizomeraza i DNA in vivo koristeći model zebrice Marta Popović IP-2024-05-9425 HRZZ
Depositing User:	Marta Popović
Date Deposited:	19 May 2026 12:16
URI:	https://fulir.irb.hr:/id/eprint/11969
DOI:	10.1093/nar/gkag324

Actions (login required)

View Item