QSER1

The QSER1 gene is found on the short arm of chromosome 11 (11p13), beginning at 32,914,792 bp and ending at 33,001,816 bp. It is 87,024 bp in length. It is located between the genes DEPDC7 and PRRG4 and is 500,000 bp downstream from the Wilms Tumor 1 gene (WT1), which is implicated in multiple pathologies.{{cite web|title=Genecards QSER1|url=http://genecards.org/cgi-bin/carddisp.pl?gene=QSER1&search=qser1}}

QSER1 is highly conserved in most species of the clade Chordata. Orthologs have been found in primates, birds, reptiles, amphibians, and fish as far back as the coelacanth, which diverged 414.9 million years ago.

QSER1 has one paralog in humans, Proline-rich 12, or PRR12. PRR12 is found on chromosome 9 at 9q13.33, which does not have known function. PRR12 is found in most chordate species as far back as the coelacanth.{{cite web|title=NCBI PRR12 Gene|url=https://www.ncbi.nlm.nih.gov/gene/57479}} The duplication event likely occurred sometime in the chordate lineage near the divergence of the coelacanth. Both PRR12 and QSER1 contain the conserved DUF4211 domain near the 3’ ends of the genes.

The promoter region for QSER1 is 683 bp in length and is found on chromosome 11 between 32,914,224 bp and 32,914,906. There is some overlap between the promoter region and the 5’ UTR of QSER1. Predicted transcription factors with conservation include (but are not limited to) EGR1, p53, E2F3, E2F4, PLAG1, NeuroD2, Myf5, IKZF1, SMAD3, KRAB, MZF1, and c-Myb.{{cite web | title = Genomatix Tools: El Dorado | url = http://www.genomatix.de/ | access-date = 2013-05-02 | archive-date = 2021-12-02 | archive-url = https://web.archive.org/web/20211202010908/https://www.genomatix.de/ | url-status = dead }}

Expression of QSER1 is seen at levels lower than 50% in many tissues. However, notable expression is seen in skeletal muscle, the appendix, trigeminal ganglia, cerebellum peduncles, pons, spinal cord, ciliary ganglion, globus pallidus, subthalamic nucleus, dorsal root ganglion, fetal liver, adrenal gland, ovary, uterus corpus, cardiac myocytes, the atrioventricular node, skin, pituitary gland, tongue, early erythroid progenitors, and tonsil.{{cite web | title = NCBI GeoProfiles db; QSER1 GDS596| url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS596:219705_at}}{{cite web|title=NCBI EST Profile db; QSER1|url=https://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Hs.369368}}

File:NCBI GeoProfiles expression data for QSER1.png

A notable decrease in QSER1 expression has been noted in renal mesangial cells in response to treatment with 25 mM glucose. This condition was studied as differential expression of genes involved in cell cycle regulation had been noted in these cells in response to high glucose levels seen with diabetes mellitus.{{cite journal | vauthors = Clarkson MR, Murphy M, Gupta S, Lambe T, Mackenzie HS, Godson C, Martin F, Brady HR | title = High glucose-altered gene expression in mesangial cells. Actin-regulatory protein gene expression is triggered by oxidative stress and cytoskeletal disassembly | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 9707–9712 | date = March 2002 | pmid = 11784718 | doi = 10.1074/jbc.M109172200 | doi-access = free }}{{cite web|title=NCBI GeoProfiles db; QSER1 GDS1891|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS1891:1427151_at}}

A different study noted overexpression of QSER1 in pathological cardiomyopathy. This condition is associated with altered expression of genes involved in immune responses, signaling, cell growth, and proliferation as well as infiltration of B lymphocytes.{{cite journal | vauthors = Galindo CL, Skinner MA, Errami M, Olson LD, Watson DA, Li J, McCormick JF, McIver LJ, Kumar NM, Pham TQ, Garner HR | title = Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure | journal = BMC Physiology | volume = 9 | issue = 23 | pages = 23 | date = December 2009 | pmid = 20003209 | pmc = 2799380 | doi = 10.1186/1472-6793-9-23 | doi-access = free }}{{cite web|title=NCBI GeoProfiles db; QSER1 GDS3596|url=https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3596:1427152_at}}

Differential expression of QSER1 is seen in multiple cancer conditions. Overexpression of QSER1 was noted in Burkitt’s Lymphoma. QSER1 expression also increases with increasing Gleason score (more advanced stages) of prostate cancer.{{cite web | title = NCBI GeoProfiles db; QSER1 GDS1746| url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS1746:219705_at}} In a study on breast cancer response to paclitaxel and fluorouracil‐doxorubicin‐cyclophosphamide chemotherapy, it was noted that breast cancer lines with higher levels of QSER1 were more likely to respond to treatment than those with underexpression of QSER1.{{cite web | title = NCBI GeoProfiles db; QSER1 GDS3721| url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3721:226265_at}}

Greater expression of QSER1 was also noted in mammary epithelial cells of immortalized cell lines than in mammary epithelial cells from cell lines with finite lifespan.{{cite web | title = NCBI GeoProfiles db; QSER1 GDS2810| url = https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS2810:219705_at}}

Over 20 stem loops are predicted in the 3’ UTR of QSER1. 16 stem loops are found within the first 800 bp of 3’ UTR.{{cite web|title=mfold|url=http://mfold.rna.albany.edu/?q=mfold/RNA-Folding-Form2.3}} The 3’ UTR is almost entirely conserved in mammals with less conservation seen in other organisms.{{cite web|title=SDSC Biology Workbench ClustalW|url=http://workbench.sdsc.edu/}}

File:QSER1 protein overview.jpg

QSER1 protein is 1735 amino acids in length.{{cite web | title = NCBI QSER1 Protein | url = https://www.ncbi.nlm.nih.gov/protein/115647981}} The composition of the peptide is significantly high in serine and glutamine: 14.7% serine residues and 8.9% glutamine.{{cite web | title = SDSC Biology Work Bench; SAPS | url = http://workbench.sdsc.edu/}}

QSER1 protein is highly conserved in chordate species.

The table below shows information on the protein orthologs.

File:Tree of QSER1 Orthologs.pdf

File:PSORT prediction of conserved nuclear localization and nuclear localization signals in QSER1 protein.png

QSER1 protein contains two high conserved domains found not only in QSER1 but also in other protein products. These include the PHA02939 domain from amino acid 1380-1440 and the DUF4211 domain from amino acid 1522-1642.{{cite web | title = NCBI Conserved domains db; DUF4211 | url = https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=206097}}{{cite web | title = NCBI Conserved domains db; PHA02939 | url = https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=165249}}

Nuclear localization was predicted by pSORT. This property was conserved from the human QSER1 to the coelacanth QSER1. Multiple conserved nuclear localization signals were also predicted within the QSER1 protein by pSORT.{{cite web|title=pSORT II Prediction|url=http://psort.hgc.jp/form2.html}}

Predictions of the QSER1 protein structure indicate that the protein contains many alpha helices.{{cite web|title=SDSC Biology Workbench; PELE|url=http://workbench.sdsc.edu/}}{{cite web|title=NCBI cBLAST; QSER1|url=https://www.ncbi.nlm.nih.gov/Structure/cblast/cblast.cgi}}{{cite web|title=Phyre2|url=http://www.sbg.bio.ic.ac.uk/~phyre/index.cgi|access-date=2013-05-02|archive-date=2021-08-25|archive-url=https://web.archive.org/web/20210825203956/http://www.sbg.bio.ic.ac.uk/~phyre/index.cgi|url-status=dead}} NCBI cBLAST predicted structural similarity between the QSER1 protein and the Schizosaccharomyces pombe (fission yeast) RNA Polymerase II A chain. The two regions of similarity occur between amino acids 56-194 and 322-546. This first region (56-194) is a regulatory region in both the human and yeast RNA Polymerase II containing multiple repeats of the sequence YSPTSPSYS. Phosphorylation of serine residues in this region regulates progression through the steps of gene transcription.{{cite journal | vauthors = Möller A, Xie SQ, Hosp F, Lang B, Phatnani HP, James S, Ramirez F, Collin GB, Naggert JK, Babu MM, Greenleaf AL, Selbach M, Pombo A | title = Proteomic analysis of mitotic RNA polymerase II reveals novel interactors and association with proteins dysfunctional in disease | journal = Molecular & Cellular Proteomics | volume = 11 | issue = 6 | pages = M111.011767 | date = June 2012 | pmid = 22199231 | pmc = 3433901 | doi = 10.1074/mcp.M111.011767 | doi-access = free }} A 3D structure was provided for this region. The structurally similar region is on the exterior of the protein molecule and forms part of the DNA binding cleft.

Further structural similarity to a viral RNA Polymerase binding protein was predicted by Phyre2. This structure is found at the very end of the protein between amino acids 1671-1735. The structure has a long region of alpha helices that were also predicted by SDSC Biology Workbench PELE. An image of the structurally similar region and sequence alignment is shown on the right. Regions before the identified structurally similar domain show two other alpha helices predicted with high confidence.

File:ExPASy NetPhos Predicted Phosphorylation Sites.png

There are 12 confirmed phosphorylation sites on the QSER1 protein. Eight are phosphoserines, one phosphotyrosine, and three phosphothreonines. Three of these sites have been shown to be phosphorylated by ATM and ATR in response in DNA damage.{{cite journal | vauthors = Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ | title = ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage | journal = Science | volume = 316 | issue = 5828 | pages = 1160–1166 | date = May 2007 | pmid = 17525332 | doi = 10.1126/science.1140321 | s2cid = 16648052 | bibcode = 2007Sci...316.1160M }} 123 other possible phosphorylation sites have been predicted using the ExPASy NetPhos tool.{{cite web|title=ExPASy NetPhos|url=http://www.cbs.dtu.dk/services/NetPhos/}}

Interaction of QSER1 protein with SUMO has been noted in multiple proteome-wide studies.{{cite journal | vauthors = Tatham MH, Matic I, Mann M, Hay RT | title = Comparative proteomic analysis identifies a role for SUMO in protein quality control | journal = Science Signaling | volume = 4 | issue = 178 | pages = rs4 | date = June 2011 | pmid = 21693764 | doi = 10.1126/scisignal.2001484 | s2cid = 649212 }}{{cite journal | vauthors = Bruderer R, Tatham MH, Plechanovova A, Matic I, Garg AK, Hay RT | title = Purification and identification of endogenous polySUMO conjugates | journal = EMBO Reports | volume = 12 | issue = 2 | pages = 142–148 | date = February 2011 | pmid = 21252943 | pmc = 3049431 | doi = 10.1038/embor.2010.206 }} Predicted SUMOylation sites have been found in QSER1 protein. Highly conserved SUMOylation sites occur with the sequence MKMD at amino acid 794, VKIE at 1057, VKTG at 1145, LKSG at 1157, VKQP at 1487, and VKAE at 1492 .{{cite web|title=ExPASy SUMOplot|url=http://www.abgent.com/sumoplot}}

File:Predicted SUMOylation Sites in QSER1 protein.png

Phosphorylation of QSER1 at three serine residues, S1228, S1231, and S1239, by ATM and ATR in response to DNA damage was found in a proteome-wide study.

Interaction of QSER1 with SUMO has been confirmed in multiple studies. The role of SUMOylation in QSER1 function is unclear. However, there may be a connection between QSER1 and SUMO in response to endoplasmic reticulum stress (often caused by accumulation of misfolded proteins). In a study on ER stress, QSER1 was tagged as an ER stress response gene with altered expression.{{cite journal | vauthors = Dombroski BA, Nayak RR, Ewens KG, Ankener W, Cheung VG, Spielman RS | title = Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells | journal = American Journal of Human Genetics | volume = 86 | issue = 5 | pages = 719–729 | date = May 2010 | pmid = 20398888 | pmc = 2869002 | doi = 10.1016/j.ajhg.2010.03.017 | url = https://genomics.med.upenn.edu/vcheung/pdfs/(33)Dombroski10.pdf | access-date = 2013-05-02 | url-status = dead | archive-url = https://web.archive.org/web/20131004221440/https://genomics.med.upenn.edu/vcheung/pdfs/(33)Dombroski10.pdf | archive-date = 2013-10-04 }} Further, in a study on SUMOylation in response to accumulated misfolded proteins and ER stress found QSER1 to be a SUMO interactant in this situation. Any connection between these two activities is unstudied and unconfirmed.

Direct interaction of QSER1 with RNA polymerase II was found in a study performed by Moller, et al. Interaction was shown to occur with the DNA-directed RNA polymerase II subunit, RPB1, of RNA polymerase II during both mitosis and interphase. Colocalization/interaction of QSER1 was shown to the regulatory region of RPB1 with 52 heptapeptide (YSPTSPSYS) repeats.

Interaction between homeobox protein NANOG and Tet methylcytosine dioxygenase 1 (TET1) has been shown to be important in establishing pluripotency during the generation of induced pluripotent stem cells. QSER1 protein was shown to interact with both NANOG and TET1.{{cite journal | vauthors = Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, Das S, Levasseur DN, Li Z, Xu M, Reik W, Silva JC, Wang J | title = NANOG-dependent function of TET1 and TET2 in establishment of pluripotency | journal = Nature | volume = 495 | issue = 7441 | pages = 370–374 | date = March 2013 | pmid = 23395962 | pmc = 3606645 | doi = 10.1038/nature11925 | bibcode = 2013Natur.495..370C }}

QSER1 was found to interact with ubiquitin in two proteome-wide substrate studies.{{cite journal | vauthors = Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP | title = Systematic and quantitative assessment of the ubiquitin-modified proteome | journal = Molecular Cell | volume = 44 | issue = 2 | pages = 325–340 | date = October 2011 | pmid = 21906983 | pmc = 3200427 | doi = 10.1016/j.molcel.2011.08.025 }}{{cite journal | vauthors = Danielsen JM, Sylvestersen KB, Bekker-Jensen S, Szklarczyk D, Poulsen JW, Horn H, Jensen LJ, Mailand N, Nielsen ML | title = Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level | journal = Molecular & Cellular Proteomics | volume = 10 | issue = 3 | pages = M110.003590 | date = March 2011 | pmid = 21139048 | pmc = 3047152 | doi = 10.1074/mcp.M110.003590 | doi-access = free }} Specific details about this interaction have not been studied.

Altered expression of QSER1 is noted in pathological cardiomyopathy, Burkitt's Lymphoma, prostate cancer, and some breast cancers mentioned above. NCBI AceView lists multiple mutations associated with other pathologies including an eight base pair and 13 base pair deletion in QSER1 associated with leiomyosarcoma of the uterus, and 57 base pair difference in a neuroblastoma. Also listed are multiple splice variants with truncated 5' and/or 3' ends often noted in cancerous conditions.{{cite web|title=NCBI AceView db; QSER1|url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=qser1&submit=Go}} Further, according to the NCBI OMIM database, multiple pathologies are associated with alterations in the 11p13 region and therefore may implicate QSER1.{{cite web|title=NCBI OMIM db; 11p13|url=https://www.ncbi.nlm.nih.gov/omim/?term=11p13}} These include Exudative Vitreoretinopathy 3,{{cite web|title=NCBI OMIM db; Exudative Vitreoretinopathy 3|url=http://omim.org/entry/605750}} Familial Candidiasis 3,{{cite web|title=NCBI OMIM db; Candidiasis, Familial 3|url=http://omim.org/entry/607644}} Centralopathic Epilepsy,{{cite web|title=NCBI OMIM db; Centralopathic Epilepsy|url=http://omim.org/entry/117100}} and Autosomal Recessive Deafness 51.{{cite web|title=NCBI OMIM db; Autosomal Recessive Deafness 51|url=http://omim.org/entry/609941}}

QSER1 was also noted as a susceptibility gene for Parkinson's disease.

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Category:Human proteins