SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Serbyn, Nataliia; Bagdiul, Ivona; Noireterre, Audrey; Michel, Agnès H.; Suhandynata, Raymond T.; Zhou, Huilin; Kornmann, Benoı̂t; Stutz, Françoise

doi:10.1016/j.celrep.2021.110034

Cited by 21 publications

(19 citation statements)

References 77 publications

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“…No consensus has emerged regarding the role of SUMO modifications for SPRTN-dependent DPC repair. SUMOylation has been suggested to block alternative repair pathways to promote SPRTN-dependent repair 26 , 27 ; while SUMOylation was found to be dispensable for SPRTN function in another study 28 . At any rate, the existence of at least two proteolytic systems to degrade DPCs - SPRTN and the proteasome - indicates significant evolutionary pressure to cope with these insults in order to preserve genome integrity.…”

Section: Introductionmentioning

confidence: 90%

SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

Weickert

Götz

et al. 2023

Nat Commun

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DNA-protein crosslinks (DPCs) are pervasive DNA lesions that are induced by reactive metabolites and various chemotherapeutic agents. Here, we develop a technique for the Purification of x-linked Proteins (PxP), which allows identification and tracking of diverse DPCs in mammalian cells. Using PxP, we investigate DPC repair in cells genetically-engineered to express variants of the SPRTN protease that cause premature ageing and early-onset liver cancer in Ruijs-Aalfs syndrome patients. We find an unexpected role for SPRTN in global-genome DPC repair, that does not rely on replication-coupled detection of the lesion. Mechanistically, we demonstrate that replication-independent DPC cleavage by SPRTN requires SUMO-targeted ubiquitylation of the protein adduct and occurs in addition to proteasomal DPC degradation. Defective ubiquitin binding of SPRTN patient variants compromises global-genome DPC repair and causes synthetic lethality in combination with a reduction in proteasomal DPC repair capacity.

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Section: Introductionmentioning

confidence: 90%

SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

Weickert

Götz

et al. 2023

Nat Commun

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“…A recent study reported that Siz2, an analog of Siz1, SUMOylates the vicinity of DPCs (chromatin-bound proteins adjacent to DPCs) to recruit Wss1, a replication-associated metalloprotease carrying the SprT domain, that binds and digests DPCs via its SIMs ( Serbyn et al, 2021 ). Another study in S. cerevisiae identified the AAA ATPase Cdc48 (also known as p97 or valosin-containing protein (VCP) in mammals) and its substrate-recruiting adaptor Ufd1/Doa1 as a binding partner of Wss1 ( Balakirev et al, 2015 ).…”

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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“…Consistent with SUMO conjugation on TOP1-DPCs ( Mao et al, 2000b ), the DPC protease activity of Wss1 (harboring SIM domains) is largely SUMO-targeted and associated with Cdc48/p97 activity ( Stingele et al, 2014 ; Balakirev et al, 2015 ) ( Figure 1G ). Interestingly, a more recent study in yeast showed that the SUMO ligase Siz2 (PIAS4 in humans) SUMOylates proteins in the vicinity of DPCs to stimulate Wss1 recruitment to the lesion ( Serbyn et al, 2021 ). Proteins associated with DNMT1 are also SUMOylated in cells following DNMT1 trapping via 5-aza-dC treatment ( Borgermann et al, 2019 ).…”

Section: Role Of Sumo In Dna-protein Crosslink Removal By Dna-protein...mentioning

confidence: 99%

Targeting DNA-Protein Crosslinks via Post-Translational Modifications

Leng

Duxin

2022

Front. Mol. Biosci.

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Covalent binding of proteins to DNA forms DNA-protein crosslinks (DPCs), which represent cytotoxic DNA lesions that interfere with essential processes such as DNA replication and transcription. Cells possess different enzymatic activities to counteract DPCs. These include enzymes that degrade the adducted proteins, resolve the crosslinks, or incise the DNA to remove the crosslinked proteins. An important question is how DPCs are sensed and targeted for removal via the most suited pathway. Recent advances have shown the inherent role of DNA replication in triggering DPC removal by proteolysis. However, DPCs are also efficiently sensed and removed in the absence of DNA replication. In either scenario, post-translational modifications (PTMs) on DPCs play essential and versatile roles in orchestrating the repair routes. In this review, we summarize the current knowledge of the mechanisms that trigger DPC removal via PTMs, focusing on ubiquitylation, small ubiquitin-related modifier (SUMO) conjugation (SUMOylation), and poly (ADP-ribosyl)ation (PARylation). We also briefly discuss the current knowledge gaps and emerging hypotheses in the field.

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SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Cited by 21 publications

References 77 publications

SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Targeting DNA-Protein Crosslinks via Post-Translational Modifications

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