The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability

Ruggiano, Annamaria; Vaz, Bruno; Kilgas, Susan; Popović, Marta; Rodriguez-Berriguete, Gonzalo; Singh, Abhay N.; Higgins, Geoff S.; Kiltie, Anne E.; Ramadan, Kristijan (2021) The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability. Cell Reports, 37 (10). ISSN 2211-1247

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Abstract

DNA-protein crosslinks (DPCs) are a specific type of DNA lesion in which proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration, and accelerated aging. DPC proteolysis was recently identified as a specialized pathway for DPC repair. The DNA-dependent protease SPRTN and the 26S proteasome emerged as two independent proteolytic systems. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the cellular response to DPC formation, we identify ubiquitylation and SUMOylation as two major signaling events in DNA replication-coupled DPC repair. DPC ubiquitylation recruits SPRTN to repair sites, promoting DPC removal. DPC SUMOylation prevents DNA double-strand break formation, HR activation, and potentially deleterious genomic rearrangements. In this way, SUMOylation channels DPC repair toward SPRTN proteolysis, which is a safer pathway choice for DPC repair and prevention of genomic instability.

Item Type:	Article
Uncontrolled Keywords:	BRCA deficiency; DNA-protein crosslink repair; DNA replication; genome stability; formaldehyde toxicity; homologous recombination; synthetic lethality; SPRTN protease; SUMO; ubiquitin
Subjects:	NATURAL SCIENCES > Biology NATURAL SCIENCES > Interdisciplinary Natural Sciences BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences INTERDISCIPLINARY AREAS OF KNOWLEDGE > Biotechnology in Biomedicine (natural science, biomedicine and healthcare, bioethics area
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
Depositing User:	Ana Zečević
Date Deposited:	27 Mar 2024 11:24
URI:	http://fulir.irb.hr/id/eprint/8746
DOI:	10.1016/j.celrep.2021.110080

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