Prognostic markers Abstract Ultraviolet light induced pyrimidine dimer is a helix distortion DNA damage type, which recruits repair complexes.
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However, proteins of these complexes that take part in both DNA damage recognition and repair have been well-described, the regulation of the downstream steps of nucleotide excision repair NER have not been clearly clarified yet.
In a high-throughput screen, we identified SerpinB2 SPB2 as one of the most dramatically upregulated gene in keratinocytes following UV irradiation. Additionally, UV damage induced translocation of SPB2 from the cytoplasm to the nucleus as well as the damage induced foci formation of it.
Finally, we demonstrated that UV irradiation promoted the association of SPB2 with ubiquitylated proteins.
In basal cell carcinoma tumour cells, we identified changes in the subcellular localization of SPB2. Based on our results, we conclude that SPB2 protein has a novel role in UV-induced NER pathway, since it regulates the removal of the repair complex from the damaged site leading to cancerous malformation. Download PDF Introduction Our genome is constantly exposed to endogenous and exogenous sources leading to DNA damage and impairment of genome integrity.
SerpinB2 is involved in cellular response upon UV irradiation | Scientific Reports
For instance, UV irradiation is an exogenous factor, which could cause formation of dimers between adjacent pyrimidine bases in the DNA 12. Nucleotide excision pikkelysömör és ízületek kezelése NER is a unique pathway for the recognition and elimination a wide inverse psoriasis pubmed of structurally diverse DNA damages, such as cyclobutene-pyrimidine dimers CPDspyrimidine-pyrimidone photoproducts PPsor chemically induced bulky adducts, intrastrand crosslinks caused by drugs, such as cisplatin and reactive oxygen species ROS induced cyclopurines 3.
However, proteins involved in NER have partially been identified, some major steps regulated by ubiquitin ligases and proteases - required for latter steps of NER - have still remained to be elucidated. Furthermore, A. Wani et al. In addition, protease inhibitors could also negatively regulate proteolytic processes.
The serine protease inhibitor superfamily, called Serpins, consists of highly heterogenic proteins taking part in tumorigenesis, blood clotting, hormone transport, inflammation, immune function and mucous production 7. Based on the sequence similarities, the Serpin superfamily is divided into 16 different clades A-P and the human Serpins are represented in the first 9 clades 8. SerpinB is the largest human Serpin clade, which consists of 13 proteins encoded in chromosome 6p25 and 18q21 regions 89.
It has been reported that protein members of the SerpinB clade regulate processes related to inflammation, immune system function, mucous production, apoptosis, tumour metastasis and autoimmunity 10 However, no data have been published about their regulatory role in DNA repair processes, yet.
SerpinB2 SPB2also known as Plasminogen activator inhibitor 2 PAI-2 was first identified from placenta and it was described as an inhibitor of the extracellular urokinase plasminogen activator uPA and tissue plasminogen activator tPA 12 SPB2 has been described as an intracellular Serpin involved in signal transduction, inhibition of apoptosis, macrophage survival, monocyte and keratinocyte differentiation, cyto-progression, or immune modulation 1415161718192021 In this study, we have identified SPB2 as one of the most dramatically upregulated gene by UV inverse psoriasis pubmed.
Here we provide evidence that the protein level of SPB2 is increased upon UV irradiation and that it is transported from the cytoplasm inverse psoriasis pubmed the nucleus short time after damage induction. In addition, we have also found differences in the subcellular localization of SPB2 between normal and tumorous parts of the examined human basal cell carcinoma tissues. These results further support our hypothesis that SPB2 could function as a repair protein in normal cells since the translocation of the protein to the nucleus is blocked in tumorous cells thereby interfering with its DNA repair function.
Results SPB2 mRNA and protein levels are increased following UV irradiation Ultraviolet light induced DNA damage response is an extensively studied process, since improper or delayed repair of the errors could lead to cancerous malformations.
In our recent study inverse psoriasis pubmed have identified UV-induced genes in an immortalized inverse psoriasis pubmed cell line, Hker E6SFM, by performing a microarray experiment By comparing the mRNA profiles of non-treated and UV treated cells, genes showed significantly altered expression.
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The means, standard deviations based on three independent experimental triplicates are indicated in case of c—e. Data were normalized to 18 S RNA. H3 was used as loading control. H3, Lamin A and Tubulin were used as loading controls. Full size image In order to analyse the expression of the SeprinB2 gene in additional cell types, we performed qPCR experiment on melanoma cell line A following UV irradiation non-treated, 2 hours, 8 hours and 24 hours after the treatment.
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As we expected, we detected a significant increase in the protein level of SPB2 2 and 8 hours after the irradiation and it decreased 24 hours following irradiation. Since we observed significant overproduction of SPB2 2 hours after UV irradiation, we tested whether the UV treatment influenced the subcellular localization of this protein.
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We performed Western blot experiment on cytoplasmic, nuclear soluble and nuclear insoluble protein fractions obtained from U2OS cells 2- and 4 hours upon UV irradiation. Under normal conditions, SPB2 is mostly localized in the cytoplasm inverse psoriasis pubmed following UV irradiation, the protein level is increased Fig.
Following UV-induced DNA damage, we detected increased SPB2 protein level in the nuclear soluble fraction 2 hours after the irradiation, while 4 hours after UV treatment the protein level returned to the steady-state level Fig. Following 2- and 4 hours UV treatments, we detected a significant higher level of SPB2 in the nucleus and we also observed that SPB2 was localized to discrete nuclear foci compared to the untreated control Fig. Similar to UV damage, we found that hydrogen-peroxide treatment 2- and 4 hours resulted in elevated SPB2 protein level in the nucleus compared to control Fig.
These data showed that SPB2 protein accumulation was observed upon only inverse psoriasis pubmed DNA damage inducing agents, which target specific nucleotides and potentially have rapid repair kinetics. DAPI blue was used to visualize the nuclei. Scale bars represent 30 µm. Only the chromatin-bound proteins were visualized. For each condition, a higher magnification of a single cell is shown on the right side of the figure.
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Arrowheads indicate the cellular position of the LacO arrays. Scale bars represent 5 µm. The success of the immunoprecipitation experiment was controlled with anti-HA antibody and the connection between SPB2 and ubiquitin was detected with anti-GFP antibody since cells were transfected with plasmid encoding SPB2-EGFP fusion protein in the precipitated samples both in control and UV treated 2 h and 4 h samples. These results support our previous experimental data that the two proteins co-localize with each other and the N-terminal part of XPB is required for the interaction.
UV damage regulates the ubiquitin mediated fine-tuning of SPB2 Ubiquitin signalling has been reported to participate in the regulation of various types of repair processes, such as UV-induced NER 6. This raises the possibility that the association of SPB2 to the NER repair complex could be also fine-tuned by post translational modifications.
To test whether the ubiquitylation mediated signalization is required for SPB2 loading to the inverse psoriasis pubmed site, we performed co-immunoprecipitation co-IP experiment on U2OS cells. In untreated cells no interaction was detected between SPB2 and Ub. These data suggest that SPB2 may be involved in ubiquitylation mediated processes upon UV irradiation.
SPB2 shows altered localization in basal cell carcinomas A recent study has showed that the SPB2 is involved in cancerous malformations by affecting metastatic tumour formation.
It was reported that the elevated expression of SPB2 resulted in a poor survival of bladder cancer patients 27or patients diagnosed with esophageal squamous cell carcinoma However, reduced expression of SPB2 also leads to reduced survival rate inverse psoriasis pubmed patients suffering from breast 293031 or pancreatic cancer It has been also shown that the loss of key players regulating NER leads to more frequent incidence of skin carcinoma and to poor prognosis for those patients 33 To reveal whether SPB2 is associated with skin tumour progression, we performed immunostaining on tissue samples obtained from basal cell carcinomas.
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However, we could not observe any significant differences in the protein level of SPB2 by comparing the tumorous parts of the tissue with the normal parts of it. We found that SPB2 was mainly found in the cytoplasm of tumorous cells, while in the non-tumorous parts of the tissue SPB2 protein showed equal distribution between the cytoplasm and nucleus.
In some cases, higher SPB2 protein level was detected in the nucleus in the normal parts of the tissues Fig. In tumorous cells SPB2 could not be transported to the nucleus and this probably leads to insufficient repair, hereby increasing the mutation rate. PC represents the phase contrast images. The N and T represent the normal and the tumorous part of the tissue, respectively. DAPI blue was used to visualize nuclei.
Scale bars represent µm b,d Quantitative evaluation of fluorescent intensity obtained from normal N and tumorous T part of the represented tissues. In each graph DAPI blue represents the nuclei. This could be explained by evolutionary conserved mechanisms in response to UV irradiation, which is inverse psoriasis pubmed emphasised in keratinocyte cells, since those are normally exposed to UV light.
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This might indicate that the activation of SPB2 upon UV irradiation is a common mechanism in different cell types, owing tissue specific repair mechanisms 353637383940upon various DNA damages affecting nucleotides and SPB2 protein could play role in the fine-tune regulation of these repair pathways. In addition, we also demonstrated that UV irradiation promoted the translocation of SPB2 to the nucleus and the formation of discrete nuclear foci at the sites of DNA repair.
Based on these data inverse psoriasis pubmed hypothesise that the subcellular localization of SPB2 protein is psoriasis skin disease contagious by the type of DNA damage or additional inverse psoriasis pubmed factors.
It was shown that infection or inflammation led to the cytoplasmic accumulation of the SPB2 protein However, upon Inverse psoriasis pubmed irradiation similar cytoplasmic distribution of SPB2 was detected, the nuclear accumulation of the protein could also be observed compared to control.
These results are in accord with a recent study described by Lee and Yerbury et al.
Additionally, the SPB2 nuclear translocation could be tightly regulated and is necessary for performing the function of the protein shown in many cases involving transcription factors, activated MAPs, Nrf2 and also for EGFR after UV irradiation 36424344 These indicate that the transport of several repair factors, and also SPB2, to the nucleus could be triggered by stress conditions affecting the integrity of the DNA, thereby promoting the process of DNA repair.
However, we did not detect physical interaction between XPB and SPB2 data not shownan indirect connection between them could not be excluded. Recently, it has been reported that an anchored NER factor can recruit other downstream NER factors and possible participant proteins to repair foci but not the upstream elements of the pathway by using LacO assay Furthermore, Salim Ziani et al. NER is a well-coordinated, highly complex pathway, that has not been clearly elucidated, yet.
Recent studies have reported that the ubiquitin-proteasome system UPS and proteases are required for the precise regulation inverse psoriasis pubmed the NER pathway 4647 These studies have demonstrated that ubiquitin-mediated regulation inverse psoriasis pubmed the NER factors is necessary only in the early steps of the repair pathway.
On the contrary, the regulatory effect of the USP7 in the mediator and effector steps of the NER pikkelysömör a kezeken népi gyógymódokkal has remained unexplored, though the direct interaction between XPB and 26S proteasome has been already described Recently SPB2 has been identified as an interacting partner of the UPS system in neurons and its loss leads to disturbance in compartmentalization of the aggregated proteins, thereby resulting in malfunction of the UPS pathway