DNA–Protein Crosslink Proteolysis Repair

Vaz, Bruno; Popović, Marta; Ramadan, Kristijan

doi:10.1016/j.tibs.2017.03.005

Cited by 80 publications

(70 citation statements)

References 105 publications

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“…The source of genome instability in both RJALS patient cells and SPRTN-deficient human and mouse cells was recently demonstrated to arise from replication stress caused by the accumulation of replication-blocking DNA-protein crosslinks (DPC) 20,22,23 . DPCs are formed by various aldehydes including the well-known DPC inducing agent formaldehyde (FA), which are by-products of metabolic processes such as lipid peroxidation or histone and DNA demethylation [31][32][33] . As SPRTN protease activity is required to cleave DPCs, defective SPRTN protease activity results in profound replication stress, visualised as increased fork stalling and significantly reduced DNA replication fork velocity.…”

Section: Introductionmentioning

confidence: 99%

SPRTN Protease and Checkpoint Kinase 1 Cross-Activation Loop Safeguards DNA Replication

Halder

Torrecilla

Burkhalter³

et al. 2018

Preprint

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The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease activity exhibit severe DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer in humans and mice. Strikingly, SPRTN-deficient cells also show a severe G2/M checkpoint defect and fail to activate a robust checkpoint kinase 1 (CHK1) signalling cascade normally triggered in response to replication stress. Here, we show that SPRTN activates the CHK1 signalling cascade during physiological (steady-state) DNA replication by proteolysis-dependent eviction of CHK1 from chromatin. The N-terminal CHK1 fragments cleaved by SPRTN protease still possess kinase activity and phosphorylate SPRTN. This CHK1-dependent phosphorylation stimulates SPRTN recruitment to chromatin to further promote CHK1 eviction from chromatin, DPC removal and unperturbed DNA replication. Our data suggest that a SPRTN-CHK1 cross-activation loop is essential for steady-state DNA replication and protection from DNA replication stress, a major source of genome instability in diseases that cause premature ageing and cancer. In addition, we disclose a mechanism of CHK1 activation during physiological DNA replication, when long stretches of single stranded (ss) DNA that are induced by genotoxic stress and activate canonical and robust CHK1 signalling are not present.

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Section: Introductionmentioning

confidence: 99%

SPRTN Protease and Checkpoint Kinase 1 Cross-Activation Loop Safeguards DNA Replication

Halder

Torrecilla

Burkhalter³

et al. 2018

Preprint

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“…DNA-protein crosslinks (DPCs) are a significant source of replicative stress (Vaz et al, 2017). GCNA belongs to the SprT domain protein family that gets its name from Spartan.…”

Section: Gcna and Spartan Act Independentlymentioning

confidence: 99%

GCNA preserves genome integrity and fertility across species

Bhargava

Goldstein

Russell

et al. 2019

Preprint

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SUMMARYThe propagation of species depends on the ability of germ cells to protect their genome in the face of numerous exogenous and endogenous threats. While these cells employ a number of known repair pathways, specialized mechanisms that ensure high-fidelity replication, chromosome segregation, and repair of germ cell genomes remain incompletely understood. Here, we identify Germ Cell Nuclear Acidic Peptidase (GCNA) as a highly conserved regulator of genome stability in flies, worms, zebrafish, and humans. GCNA contains a long acidic intrinsically disordered region (IDR) and a protease-like SprT domain. In addition to chromosomal instability and replication stress, GCNA mutants accumulate DNA-protein crosslinks (DPCs). GCNA acts in parallel with a second SprT domain protein Spartan. Structural analysis reveals that while the SprT domain is needed to limit meiotic and replicative damage, most of GCNA’s function maps to its IDR. This work shows GCNA protects germ cells from various sources of damage, providing novel insights into conserved mechanisms that promote genome integrity across generations.HighlightsGCNA ensures genomic stability in germ cells and early embryos across speciesGCNA limits replication stress and DNA double stranded breaksGCNA restricts DNA-Protein Crosslinks within germ cells and early embryosThe IDR and SprT domains of GCNA govern distinct aspects of genome integrityGraphic Abstract

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“…DNA-protein crosslinks (DPCs) are ubiquitous and heterogeneous DNA lesions that arise from irreversible, covalent binding of a protein to DNA following exposure to a chemical or physical crosslinking agent, e.g. formaldehyde or UV light (Fielden et al, 2018;Ide et al, 2018;Vaz et al, 2017). Formaldehyde is a cellular by-product of methanol metabolism, histone demethylation and lipid peroxidation as well as an environmental pollutant.…”

Section: Introductionmentioning

confidence: 99%

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

Vaz

Ruggiano

Popović

et al. 2020

Preprint

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max 150 words) DNA-protein crosslinks (DPCs) are a specific type of DNA lesions where proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, cancer, neurodegeneration and accelerated ageing. DPC proteolysis was recently discovered as a specialised pathway for DPC repair. The DNA-dependent SPRTN protease and 26S proteasome emerged as as two independent proteolytic systems for DPC repair. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the role of ubiquitin and SUMO in DPC repair, we identified mutually exclusive signalling mechanisms associated with DPC repair pathway choice. DPC modification by SUMO-1 favours SPRTN proteolysis as the preferred pathway for DPC repair. DPC SUMOylation counteracts DPC ubiquitination, which promotes DNA breaks and the switch toHR. We propose that modification of DPCs by SUMO-1 promotes SPRTN proteolysis, which is essential for DPC removal to prevent DNA replication defects, chromosomal recombination and genomic instability.

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DNA–Protein Crosslink Proteolysis Repair

Cited by 80 publications

References 105 publications

SPRTN Protease and Checkpoint Kinase 1 Cross-Activation Loop Safeguards DNA Replication

SPRTN Protease and Checkpoint Kinase 1 Cross-Activation Loop Safeguards DNA Replication

GCNA preserves genome integrity and fertility across species

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

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