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

Ruggiano, Annamaria; Vaz, Bruno; Kilgas, Susan; Popović, Marta; Rodríguez-Berriguete, Gonzalo; Singh, Abhay Narayan; Higgins, Geoff S.; Kiltie, Anne E.; Ramadan, Kristijan

doi:10.1016/j.celrep.2021.110080

Cited by 38 publications

(39 citation statements)

References 68 publications

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“…It is therefore conjectured that, upon TOP-DPC SUMOylation and ubiquitylation by the Siz1–Slx5/8 pathway, the Cdc48 complex binds the heterologous SUMO–ubiquitin chain and unfolds TOP-DPCs to facilitate their digestion by Wss1. In mammalian cells, SUMOylation was shown to channel DPC repair pathway(s) to SPRTN, the ortholog of Wss1, during DNA replication ( Ruggiano et al, 2021 ). Unlike Wss1, SPRTN lacks SIM but is still able to interact with both ubiquitin and SUMO moieties conjugated to DPCs.…”

Section: Sumoylation In the Repair Of Topoisomerase-mediated Dna Damagementioning

confidence: 99%

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Sun

Nitiss

Pommier

2022

Front. Mol. Biosci.

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Topoisomerases play crucial roles in DNA metabolism that include replication, transcription, recombination, and chromatin structure by manipulating DNA structures arising in double-stranded DNA. These proteins play key enzymatic roles in a variety of cellular processes and are also likely to play structural roles. Topoisomerases allow topological transformations by introducing transient breaks in DNA by a transesterification reaction between a tyrosine residue of the enzyme and DNA. The cleavage reaction leads to a unique enzyme intermediate that allows cutting DNA while minimizing the potential for damage-induced genetic changes. Nonetheless, topoisomerase-mediated cleavage has the potential for inducing genome instability if the enzyme-mediated DNA resealing is impaired. Regulation of topoisomerase functions is accomplished by post-translational modifications including phosphorylation, polyADP-ribosylation, ubiquitylation, and SUMOylation. These modifications modulate enzyme activity and likely play key roles in determining sites of enzyme action and enzyme stability. Topoisomerase-mediated DNA cleavage and rejoining are affected by a variety of conditions including the action of small molecules, topoisomerase mutations, and DNA structural forms which permit the conversion of the short-lived cleavage intermediate to persistent topoisomerase DNA–protein crosslink (TOP-DPC). Recognition and processing of TOP-DPCs utilizes many of the same post-translational modifications that regulate enzyme activity. This review focuses on SUMOylation of topoisomerases, which has been demonstrated to be a key modification of both type I and type II topoisomerases. Special emphasis is placed on recent studies that indicate how SUMOylation regulates topoisomerase function in unperturbed cells and the unique roles that SUMOylation plays in repairing damage arising from topoisomerase malfunction.

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Section: Sumoylation In the Repair Of Topoisomerase-mediated Dna Damagementioning

confidence: 99%

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Sun

Nitiss

Pommier

2022

Front. Mol. Biosci.

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“…A subsequent study further demonstrated the relative roles of SPRTN versus the proteasome in DPC repair in Xenopus egg extracts. It was found that SPRTN and the proteasome are distinct pathways that act independently from each other (Larsen et al, 2019 ; Ruggiano et al, 2021 ). SPRTN recruitment requires DPC SUMOylation (Ruggiano et al, 2021 ) and the presence of a DNA polymerase on one side and a short tract of ssDNA on the other side of a DPC in order to prevent indiscriminate destruction of replisome components and chromatin proteins (Larsen et al, 2019 ).…”

Section: Contribution Of Proteases To the Hallmarks Of Agingmentioning

confidence: 99%

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

et al. 2022

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Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age‐associated diseases. The ubiquitin–proteasome and autophagy‐lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age‐related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy‐lysosome and ubiquitin–proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age‐related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age‐related neurodegeneration.

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“…Alternatively, if the polymerase extends the nascent DNA to within a few nucleotides of the lesion, SPRTN-mediated DPC proteolysis is activated to degrade modified or unmodified DPCs. The remaining peptide-DNA adduct can be bypassed by TLS polymerases and repaired post-replication ( Larsen et al, 2019 ; Sparks et al, 2019 ; Ruggiano et al, 2021 ). Created in BioRender.com .…”

Section: Mechanisms Of Dpc Repairmentioning

confidence: 99%

“…A recent study demonstrated that both DPC ubiquitination and SUMOylation promote DPC repair by SPRTN. DPC ubiquitination signals SPRTN recruitment to DPC sites and DPC SUMOylation prevents activation of HR to promote DPC repair by SPRTN ( Ruggiano et al, 2021 ). Thus, SPRTN promotes repair of unmodified, ubiquitinated, and SUMOylated DPCs.…”

Section: Mechanisms Of Dpc Repairmentioning

confidence: 99%

“…Ubiquitinated DPCs induced by formaldehyde treatment are recognized by the SPRTN UBZ motif and the UBZ domain is required for its proper localization to ubiquitinated DPC repair sites. However, overexpression of SPRTN ΔUBZ mutant in SPRTN depleted cells only partially rescued DPC levels ( Ruggiano et al, 2021 ). Studies in Xenopus extracts revealed that proficient cleavage of DPCs by SPRTN occurs even when DPC ubiquitination is prevented ( Larsen et al, 2019 ).…”

Section: Regulation Of Sprtn Protease and Sprtn-mediated Dpc Proteolysismentioning

confidence: 99%

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Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease

Perry

Ghosal

2022

Front. Mol. Biosci.

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DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive oxygen species, aldehydes and metabolites, radiation, and chemotherapeutic drugs. Unrepaired DPCs are blockades to all DNA metabolic processes. Specifically, during DNA replication, replication forks stall at DPCs and are vulnerable to fork collapse, causing DNA breakage leading to genome instability and cancer. Replication-coupled DPC repair involves DPC degradation by proteases such as SPRTN or the proteasome and the subsequent removal of DNA-peptide adducts by nucleases and canonical DNA repair pathways. SPRTN is a DNA-dependent metalloprotease that cleaves DPC substrates in a sequence-independent manner and is also required for translesion DNA synthesis following DPC degradation. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, indicating the critical role for SPRTN and DPC repair pathway in genome maintenance. In this review, we will discuss the mechanism of replication-coupled DPC repair, regulation of SPRTN function and its implications in human disease and cancer.

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

Cited by 38 publications

References 68 publications

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease

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