Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging

Huang, Jinzhou; Zhou, Qin; Gao, Ming; Nowsheen, Somaira; Zhao, Fei; Kim, Wootae; Zhu, Qian; Kojima, Yoshitane; Yin, Ping; Zhang, Yong; Guo, Guijie; Tu, Xinyi; Deng, Min; Luo, Kuntian; Qin, Bo; Machida, Yuichi; Lou, Zhenkun

doi:10.1016/j.molcel.2020.06.027

Cited by 40 publications

(44 citation statements)

References 37 publications

(73 reference statements)

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“…Of note, while this study was under consideration, it was proposed that SPRTN is deubiquitylated by VCPIP1 ( 29 ). In addition, a recent preprint argued that USP11 is responsible for SPRTN deubiquitylation ( 30 ).…”

Section: Resultsmentioning

confidence: 99%

A ubiquitin switch controls autocatalytic inactivation of the DNA–protein crosslink repair protease SPRTN

Zhao

Kieser

et al. 2020

Nucleic Acids Research

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Repair of covalent DNA–protein crosslinks (DPCs) by the metalloprotease SPRTN prevents genome instability, premature aging and carcinogenesis. SPRTN is specifically activated by DNA structures containing single- and double-stranded features, but degrades the protein components of DPCs promiscuously and independent of amino acid sequence. This lack of specificity is useful to target diverse protein adducts, however, it requires tight control in return, in order to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover the components and principles of a ubiquitin switch, which negatively regulates SPRTN. We demonstrate that monoubiquitylation is induced in an E3 ligase-independent manner and, in contrast to previous assumptions, does not control chromatin access of the enzyme. Data obtained in cells and in vitro reveal that monoubiquitylation induces inactivation of the enzyme by triggering autocatalytic cleavage in trans while also priming SPRTN for proteasomal degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs.

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Section: Resultsmentioning

confidence: 99%

A ubiquitin switch controls autocatalytic inactivation of the DNA–protein crosslink repair protease SPRTN

Zhao

Kieser

et al. 2020

Nucleic Acids Research

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“…DPC proteases can themselves be modified for regulatory purposes. SPRTN exists in a mono-ubiquitylated form, but exposure to FA leads to its de-ubiquitylation—two different studies have identified the de-ubiquitylating enzymes VCPIP and USP11—and acetylation to allow recruitment to chromatin 4 , 64 , 65 .…”

Section: Dpc Proteasesmentioning

confidence: 99%

DNA–protein crosslink proteases in genome stability

Ruggiano

Ramadan

2021

Commun Biol

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Proteins covalently attached to DNA, also known as DNA–protein crosslinks (DPCs), are common and bulky DNA lesions that interfere with DNA replication, repair, transcription and recombination. Research in the past several years indicates that cells possess dedicated enzymes, known as DPC proteases, which digest the protein component of a DPC. Interestingly, DPC proteases also play a role in proteolysis beside DPC repair, such as in degrading excess histones during DNA replication or controlling DNA replication checkpoints. Here, we discuss the importance of DPC proteases in DNA replication, genome stability and their direct link to human diseases and cancer therapy.

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“…VCPIP1 was also a strong hit implicated in DNA repair. VCPIP1 is a deubiquitinase that is activated by ATM/ATR and involved in the removal of protein-DNA crosslinks through the regulation of SPRTN, that is critical for damage prevention during DNA replication[70,71]. In addition, the gene encoding the Protein phosphatase 2A subunit (PPP2R2A) was negatively selected.…”

Section: Resultsmentioning

confidence: 99%

Loss of HMCES is synthetic lethal with APOBEC activity in cancer cells

Biayna

Garcı́a-Cao

et al. 2021

Preprint

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Analysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here we report the implementation of CRISPR/Cas9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression specifically in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation, oxidative stress and ATR inhibition; strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A expressing tumors.

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Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging

Cited by 40 publications

References 37 publications

A ubiquitin switch controls autocatalytic inactivation of the DNA–protein crosslink repair protease SPRTN

A ubiquitin switch controls autocatalytic inactivation of the DNA–protein crosslink repair protease SPRTN

DNA–protein crosslink proteases in genome stability

Loss of HMCES is synthetic lethal with APOBEC activity in cancer cells

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