The Critical Roles of the SUMO-Specific Protease SENP3 in Human Diseases and Clinical Implications

The activation of DNA‐dependent kinase (DNA‐PKcs) upon DNA damage contains a cascade of reactions, covering acetylation by TIP60, binding with Ku70/80, and autophosphorylation. However, how cells regulate TIP60‐mediated acetylation of DNA‐PKcs and the following DNA‐PKcs activation upon DNA damage remains obscure. This present study reported that TIP60 is hyper‐SUMOylated in normal conditions, but upon irradiation‐induced DNA damage, small ubiquitin‐like modifier (SUMO)‐specific protease 3 (SENP3)‐mediated deSUMOylation of TIP60 promoted its interaction with DNA‐PKcs to form the TIP60‐DNA‐PKcs complex. We show that TIP60 SUMOylation is reduced quickly in response to DNA damage and the deSUMOylation of TIP60 by SENP3 is required for DNA‐PKcs acetylation and its autophosphorylation. Comet and γH2AX immunofluorescence assay showed that knockdown of SENP3 impaired DNA damage repair. Using the NHEJ report system, we found that knockdown of SENP3 affected the efficiency of NHEJ. Further exploration using clonogenic survival assay, cell viability assay and cytoflow assay suggested that leaking SENP3 increased the sensitivity of tumour cells to serval DNA damage treatment. Overall, our findings revealed a previously unidentified role of SENP3 in regulating DNA‐PKcs activity and DNA damage repair.

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“… 17 Also, SENP3 has been reported to deSUMOylate NPM1, promoting BRCA1 recruitment and HR repair in response to DNA damage. 18 , 19 …”

Section: Introductionmentioning

confidence: 99%

SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair

Yang

Huang

Cao

et al. 2022

MedComm

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“…Limited knowledge exists in the literature on the mechanistic role of SENP3 in milk production or morphological udder development. Given its widespread roles in protein stability, chromatin organisation, transcription, DNA repair, autophagy, protein localisation and homeostasis, a number of potential mechanisms maybe of interest [33]. Attributing causality to either of these mutations will require further genotyping of these variants within a study population that contain sufficient meioses to separate out causative haplotypes and appropriate functionality testing.…”

Section: Discussionmentioning

confidence: 99%

A Capra hircus chromosome 19 locus linked to milk production influences mammary conformation

Jiang

Ankersmit-Udy

Turner

et al. 2022

J Animal Sci Biotechnol

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Background Economically important milk production traits including milk volume, milk fat and protein yield vary considerably across dairy goats in New Zealand. A significant portion of the variation is attributable to genetic variation. Discovery of genetic markers linked to milk production traits can be utilised to drive selection of high-performance animals. A previously reported genome wide association study across dairy goats in New Zealand identified a quantitative trait locus (QTL) located on chromosome 19. The most significantly associated single nucleotide polymorphism (SNP) marker for this locus is located at position 26,610,610 (SNP marker rs268292132). This locus is associated with multiple milk production traits including fat, protein and volume. The predicted effect of selection for the beneficial haplotype would result in an average production increase of 2.2 kg fat, 1.9 kg protein and 73.6 kg milk yield. An outstanding question was whether selection for the beneficial allele would co-select for any negative pleiotropic effects. An adverse relationship between milk production and udder health traits has been reported at this locus. Therefore, a genome wide association study was undertaken looking for loci associated with udder traits. Results The QTL and production associated marker rs268292132 was identified in this study to also be associated with several goat udder traits including udder depth (UD), fore udder attachment (FUA) and rear udder attachment (RUA). Our study replicates the negative relationship between production and udder traits with the high production allele at position 19:26,610,610 (SNP marker rs268292132) associated with an adverse change in UD, FUA and RUA. Conclusions Our study has confirmed the negative relationship between udder traits and production traits in the NZ goat population. We have found that the frequency of the high production allele is relatively high in the NZ goat population, indicating that its effect on udder conformation is not significantly detrimental on animal health. It will however be important to monitor udder conformation as the chromosome 19 locus is progressively implemented for marker assisted selection. It will also be of interest to determine if the gene underlying the production QTL has a direct effect on mammary gland morphology or whether the changes observed are a consequence of the increased milk volume.

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“…The nucleus plays a critical role in sensing and orchestrating the overall host responses to stress. Several nuclear proteins have been shown to act as important stress-sensors in the cell, including the sentrin specific protease 3 (SENP3) which is also involved in regulation of cell cycle, survival pathways and ribosomal biogenesis (2). SENP3 functions as a processing enzyme for the SUMO2/3 precursor and as a deconjugase of SUMOylated substrates.…”

Section: Introductionmentioning

confidence: 99%

The uniqueBrucellaeffectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins

Louche

Blanco

Tls

et al. 2021

Preprint

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The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. The mechanisms controlling nuclear protein localisation in the context of stress responses induced upon bacterial infection are still poorly understood. Here we show that theBrucella abortuseffectors NyxA and NyxB interfere with the host sentrin specific protease 3 (SENP3), which is essential for intracellular replication. Translocated Nyx effectors directly interact with SENP3viaa defined acidic patch identified from the crystal structure of NyxB, preventing its nucleolar localisation at the late stages of the infection. By sequestering SENP3, the Nyx effectors induce the cytoplasmic accumulation of the nucleolar AAA-ATPase NVL, the large subunit ribosomal protein L5 (RPL5) and the ribophagy receptor NUFIP1 in Nyx-enriched structures in the vicinity of replicating bacteria. This shuttling of ribosomal biogenesis-associated nucleolar proteins is negatively regulated by SENP3 and dependent on the autophagy-initiation protein Beclin1, indicative of a ribophagy-derived process induced duringBrucellainfection. Our results highlight a new nucleomodulatory function by two uniqueBrucellaeffectors, and reveal that SENP3 is a critical regulator of the subcellular localisation of multiple nucleolar proteins duringBrucellainfection, promoting intracellular replication.

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The Critical Roles of the SUMO-Specific Protease SENP3 in Human Diseases and Clinical Implications

Cited by 18 publications

References 127 publications

SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair

SENP3‐mediated TIP60 deSUMOylation is required for DNA‐PKcs activity and DNA damage repair

A Capra hircus chromosome 19 locus linked to milk production influences mammary conformation

The uniqueBrucellaeffectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins

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