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Updated: Apr 21, 2026

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

Cecile Otten1, Marin Kutnjak1, Christine Supina-Pavic1

  • 1Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.

Nucleic Acids Research
|April 20, 2026
PubMed

Insights

DNA-protein crosslink repair (DPCR) is crucial for preventing genomic instability. This study reveals that the protease ACRC is essential for DPCR and vertebrate development by removing toxic DNA-protein crosslinks.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • DNA-protein crosslinks (DPCs) are toxic lesions that impede DNA replication and transcription.
  • Impaired DNA-protein crosslink repair (DPCR) leads to genomic instability, cell death, and is linked to cancer, aging, and neurodegeneration.
  • The organismal mechanisms of DPCR remain largely unknown, particularly the role of proteases.

Purpose of the Study:

  • To investigate the role of the putative protease ACRC/GCNA (ACidic Repeat Containing/Germ Cell Nuclear Antigen) in DNA-protein crosslink repair (DPCR) at the organismal level.
  • To create and utilize a viable animal model for studying ACRC function in adult tissues.
  • To identify the substrates of ACRC in the context of DPCR.

Main Methods:

  • CRISPR/Cas9 gene editing was used to create two zebrafish lines with inactivated Acrc.
  • Acrc-WT messenger RNA injection was employed to overcome early embryonic lethality and generate viable animal models.
  • Putative DPC substrates of ACRC were identified through experimental characterization.

Main Results:

  • ACRC is essential for vertebrate development, with its inactivation causing embryonic lethality.
  • A viable zebrafish model for studying ACRC in adult tissues was successfully generated.
  • Histone H3, topoisomerases 1 and 2, Dnmt1, Parp1, Polr3a, and Mcm2 were identified as putative DPC substrates of ACRC.
  • The essential role of ACRC in development is attributed to its function in DPC removal.

Conclusions:

  • ACRC plays a critical, evolutionarily conserved role in DNA-protein crosslink repair (DPCR) and vertebrate development.
  • ACRC functions as a protease essential for removing toxic DNA-protein crosslinks, thereby maintaining genomic integrity.
  • This study provides the first organismal insights into ACRC's function in DPCR, identifying key substrates and establishing a valuable model system for future research.

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