Structure-specific endonuclease activity of SNM1A enables processing of a DNA interstrand crosslink

Buzon, Beverlee; Grainger, Ryan A.; Huang, Simon; Rzadki, Cameron; Junop, M.S.

doi:10.1093/nar/gky759

Cited by 20 publications

(12 citation statements)

References 47 publications

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“…FAN1mediated cleavage of ICL-containing substrates in vitro is reminiscent of the activity of SNM1A, the human homolog of Pso2, a structure-specific nuclease involved in ICL repair in S. pombe [60]. To date, SNM1A and FAN1 are the only established nucleases that can traverse crosslinks and exhibit both 5'-flap endo-nuclease and 5'-3' exo-nuclease activities [53,61]. Human SNM1A complements the ICL sensitivity in yeast that lack Pso2 [60], but its deficiency confers very mild crosslink sensitivity in mammalian cells [32], probably because of the redundancy with FAN1.…”

Section: Fan1 and Dna Repair-related Processesmentioning

confidence: 99%

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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FAN1 encodes a DNA repair nuclease. Genetic deficiencies, copy number variants, and single nucleotide variants of FAN1 have been linked to karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (autism, schizophrenia, and epilepsy), cancer, and most recently repeat expansion diseases. For seven CAG repeat expansion diseases (Huntington’s disease (HD) and certain spinocerebellar ataxias), modification of age of onset is linked to variants of specific DNA repair proteins. FAN1 variants are the strongest modifiers. Non-coding disease-delaying FAN1 variants and coding disease-hastening variants (p.R507H and p.R377W) are known, where the former may lead to increased FAN1 levels and the latter have unknown effects upon FAN1 functions. Current thoughts are that ongoing repeat expansions in disease-vulnerable tissues, as individuals age, promote disease onset. Fan1 is required to suppress against high levels of ongoing somatic CAG and CGG repeat expansions in tissues of HD and FMR1 transgenic mice respectively, in addition to participating in DNA interstrand crosslink repair. FAN1 is also a modifier of autism, schizophrenia, and epilepsy. Coupled with the association of these diseases with repeat expansions, this suggests a common mechanism, by which FAN1 modifies repeat diseases. Yet how any of the FAN1 variants modify disease is unknown. Here, we review FAN1 variants, associated clinical effects, protein structure, and the enzyme’s attributed functional roles. We highlight how variants may alter its activities in DNA damage response and/or repeat instability. A thorough awareness of the FAN1 gene and FAN1 protein functions will reveal if and how it may be targeted for clinical benefit.

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Section: Fan1 and Dna Repair-related Processesmentioning

confidence: 99%

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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“…Their coordinated action in ICL unhooking was shown; the XPF-ERCC1-generated nick provided an entry point for SNM1A exonuclease activity ( Wang et al, 2011 ). Recently, SNM1A has been shown to have single-strand-specific endonuclease activity as well (5′ and 3′overhangs, hairpins, flaps, and gapped substrates) ( Buzon et al, 2018 ).…”

Section: Structure-specific Nucleases As Executors Of Icl Unhooking Amentioning

confidence: 99%

Coordinated Cut and Bypass: Replication of Interstrand Crosslink-Containing DNA

Dudás

Tick

et al. 2021

Front. Cell Dev. Biol.

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DNA interstrand crosslinks (ICLs) are covalently bound DNA lesions, which are commonly induced by chemotherapeutic drugs, such as cisplatin and mitomycin C or endogenous byproducts of metabolic processes. This type of DNA lesion can block ongoing RNA transcription and DNA replication and thus cause genome instability and cancer. Several cellular defense mechanism, such as the Fanconi anemia pathway have developed to ensure accurate repair and DNA replication when ICLs are present. Various structure-specific nucleases and translesion synthesis (TLS) polymerases have come into focus in relation to ICL bypass. Current models propose that a structure-specific nuclease incision is needed to unhook the ICL from the replication fork, followed by the activity of a low-fidelity TLS polymerase enabling replication through the unhooked ICL adduct. This review focuses on how, in parallel with the Fanconi anemia pathway, PCNA interactions and ICL-induced PCNA ubiquitylation regulate the recruitment, substrate specificity, activity, and coordinated action of certain nucleases and TLS polymerases in the execution of stalled replication fork rescue via ICL bypass.

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“… 19 SNM1A has 5′–3′ 5′ phosphate-dependent exonuclease activity and structure-specific endonuclease activity. 22 , 23 It is uncertain at what point SNM1A uses these activities, particularly during the unhooking process. While the precise function of SNM1A in ICL repair is unclear, the fact that catalytically active SNM1A is needed for repair makes SNM1A an ideal target for inhibition to specifically sensitize cells to ICL-inducing agents.…”

Section: Introductionmentioning

confidence: 99%

Identification of Bioactive SNM1A Inhibitors

et al. 2021

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SNM1A is a nuclease required to repair DNA interstrand cross-links (ICLs) caused by some anticancer compounds, including cisplatin. Unlike other nucleases involved in ICL repair, SNM1A is not needed to restore other forms of DNA damage. As such, SNM1A is an attractive target for selectively increasing the efficacy of ICL-based chemotherapy. Using a fluorescence-based exonuclease assay, we screened a bioactive library of compounds for inhibition of SNM1A. Of the 52 compounds initially identified as hits, 22 compounds showed dose–response inhibition of SNM1A. An orthogonal gel-based assay further confirmed nine small molecules as SNM1A nuclease activity inhibitors with IC 50 values in the mid-nanomolar to low micromolar range. Finally, three compounds showed no toxicity at concentrations able to significantly potentiate the cytotoxicity of cisplatin. These compounds represent potential leads for further optimization to sensitize cells toward chemotherapeutic agents inducing ICL damage.

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Structure-specific endonuclease activity of SNM1A enables processing of a DNA interstrand crosslink

Cited by 20 publications

References 47 publications

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Coordinated Cut and Bypass: Replication of Interstrand Crosslink-Containing DNA

Identification of Bioactive SNM1A Inhibitors

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