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CLSPN (claspin)

Written2012-10Linda Mannini
Istituto di Ricerca Genetica e Biomedica CNR, Pisa, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_namesclaspin homolog (Xenopus laevis)
Other alias
HGNC (Hugo) CLSPN
LocusID (NCBI) 63967
Atlas_Id 40105
Location 1p34.3  [Link to chromosome band 1p34]
Location_base_pair Starts at 35732112 and ends at 35769950 bp from pter ( according to hg19-Feb_2009)  [Mapping CLSPN.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CLSPN (1p34.3) / CANX (5q35.3)CLSPN (1p34.3) / CLSPN (1p34.3)NIPBL (5p13.2) / CLSPN (1p34.3)
Note Claspin is a S-phase checkpoint factor that is activated in response to replication stress or other DNA damage induced by genotoxic agents.

DNA/RNA

 
  Figure 1. Schematic representation of the Claspin with the two transcript variants. The transcript variant 1 with 25 exons and the transcript variant 2 with 24 exons. The exons are indicated by boxes and introns by lines.
Description The gene spans approximately 37 kb and contains 25 exons.
Transcription There are different transcripts variants, five of them encode for different isoforms. Two transcript variants encode for known proteins. The transcript variant 1 of 4769 bp counts 25 exons. The transcript variant 2 of 3977 bp, counts 24 exons (lacks 1 exon maintaining the frame).

Protein

Note The transcript variant 1 encodes for a protein of 1339 aminoacids. The transcript variant 2 encodes for a protein of 1275 amino acids.
Expression Claspin peaks at S/G2 phase in response to DNA replication blocks and DNA damage.
Localisation Claspin is located in the nucleus and it associates with Chk1 following replication fork stress or other types of DNA damage.
 
  Figure 2. Claspin regulation during DNA damage checkpoint response pathway. Upon DNA damage, ATR activates Claspin, promoting the activation of the effector kinase Chk1. Once the damage is repaired, Plk1 binds and phosphorylates Claspin favoring its proteasomal degradation.
Function Claspin is a S-phase checkpoint regulator required in response to DNA replication stress and to DNA damage induced by UV and irradiation (Chini and Chen, 2003; Sar et al., 2004; Freire et al., 2006; Tanaka, 2010). Claspin is a mediator of ATR-Chk1 signaling cascade triggers for cell cycle checkpoint activation in DNA damage response. Claspin becomes phosphorylated and interacts with Chk1 promoting its activation by ATR-dependent phosphorylation (Chini and Chen, 2004; Kumagai and Dunphy, 2003; Clarke and Clarke, 2005). Claspin also interacts with the checkpoint proteins ATR and RAd9, and ATR regulates Claspin phosphorylation in presence of DNA damage induced by genotoxic stress including UV, IR and hydroxyurea, resulting in recruitment and phosphorylation of BRCA1 (Jeong et al., 2003; Lin et al., 2004; Sørensen et al., 2004). When DNA damage has been repaired, Claspin response is turned off by ubiquitin proteasome pathway in order to inactivate checkpoint response and facilitate cells to enter the cell cycle. Therefore Claspin is phosphorylated by Plk1 kinase to permit its interaction with SCFβTrCP ubiquitin ligase that promotes its degradation (Mailand et al., 2006; Mamely et al., 2006; Peschiaroli et al., 2006). Claspin has also been found associated to replication forks in absence of DNA damage suggesting a function as a sensor required for replication fork stability (Sørensen et al., 2004; Petermann et al., 2008; Scorah et al., 2009). Finally it has been observed a role of the Claspin in genome stability. Inhibition of the Claspin by RNA interference leads to both chromosome alterations and fragile site expression in human cells. Following aphidicolin treatment, Claspin increases due to its requirement to checkpoint activation, while its synthesis decrement after a prolonged aphidicolin treatment. It has been proposed that, following an extreme replication block, Claspin allows rare cells to escape checkpoint mechanisms and enter mitosis although their genome has not yet fully replicated (Focarelli et al., 2009).
Homology This gene is present in S. cerevisiae as scMrc1; in S. pombe as spMrc1; in vertebrates as Claspin.

Mutations

Germinal - First study that reports the mutation screening of the CLSPN gene in familial breast cancer cases identifying different sequence changes (Erkko et al., 2008). Nevertheless no of these mutations is related to breast cancer susceptibility.
- Sequence variants of Claspin have been identified in different human cancers. Eight nonsynonymous variants were found from the germline of two cancer-prone individuals and five cancer cells lines of breast, ovarian, and hematopoietic origin (Zhang et al., 2009).

Implicated in

Note
  
Entity Various cancers
Note Claspin expression levels increased in cancer cells lines and tumor specimens in a study performed in normal fibroblasts and various cancer cell lines, and from tumor and normal tissues of patients with primary epithelial carcinomas, in order to evaluate Claspin as a proliferation marker (Tsimaratou et al., 2007).
  
  
Entity Breast cancer
Note Transcript levels of Claspin were highly detected in tumor breast cancer tissues in which estrogen receptor and progesterone receptor was lost (Verlinden et al., 2007).
  
  
Entity Cervical cancer
Note Claspin expression is found significantly high in cervical cancer cell lines and the analysis of its expression could be clinically relevant in the diagnosis of Human Papillomavirus-related high grade lesions of uterine cervix (Benevolo et al., 2012).
  

Bibliography

Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix.
Benevolo M, Musio A, Vocaturo A, Dona MG, Rollo F, Terrenato I, Carosi M, Pescarmona E, Vocaturo G, Mottolese M.
J Transl Med. 2012 Jun 25;10:132. doi: 10.1186/1479-5876-10-132.
PMID 22731782
 
Claspin, a regulator of Chk1 in DNA replication stress pathway.
Chini CC, Chen J.
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1033-7. (REVIEW)
PMID 15279790
 
DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system.
Clarke CA, Clarke PR.
Biochem J. 2005 Jun 1;388(Pt 2):705-12.
PMID 15707391
 
Germline alterations in the CLSPN gene in breast cancer families.
Erkko H, Pylkas K, Karppinen SM, Winqvist R.
Cancer Lett. 2008 Mar 8;261(1):93-7.
PMID 18077083
 
Claspin inhibition leads to fragile site expression.
Focarelli ML, Soza S, Mannini L, Paulis M, Montecucco A, Musio A.
Genes Chromosomes Cancer. 2009 Dec;48(12):1083-90. doi: 10.1002/gcc.20710.
PMID 19760606
 
Claspin: timing the cell cycle arrest when the genome is damaged.
Freire R, van Vugt MA, Mamely I, Medema RH.
Cell Cycle. 2006 Dec;5(24):2831-4. Epub 2006 Dec 15. (REVIEW)
PMID 17172868
 
Phosphorylated claspin interacts with a phosphate-binding site in the kinase domain of Chk1 during ATR-mediated activation.
Jeong SY, Kumagai A, Lee J, Dunphy WG.
J Biol Chem. 2003 Nov 21;278(47):46782-8. Epub 2003 Sep 8.
PMID 12963733
 
Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1.
Kumagai A, Dunphy WG.
Nat Cell Biol. 2003 Feb;5(2):161-5.
PMID 12545175
 
Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.
Lin SY, Li K, Stewart GS, Elledge SJ.
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6484-9. Epub 2004 Apr 19.
PMID 15096610
 
Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress.
Mailand N, Bekker-Jensen S, Bartek J, Lukas J.
Mol Cell. 2006 Aug 4;23(3):307-18.
PMID 16885021
 
Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery.
Mamely I, van Vugt MA, Smits VA, Semple JI, Lemmens B, Perrakis A, Medema RH, Freire R.
Curr Biol. 2006 Oct 10;16(19):1950-5. Epub 2006 Aug 24.
PMID 16934469
 
SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response.
Peschiaroli A, Dorrello NV, Guardavaccaro D, Venere M, Halazonetis T, Sherman NE, Pagano M.
Mol Cell. 2006 Aug 4;23(3):319-29.
PMID 16885022
 
Claspin promotes normal replication fork rates in human cells.
Petermann E, Helleday T, Caldecott KW.
Mol Biol Cell. 2008 Jun;19(6):2373-8. doi: 10.1091/mbc.E07-10-1035. Epub 2008 Mar 19.
PMID 18353973
 
Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures.
Sar F, Lindsey-Boltz LA, Subramanian D, Croteau DL, Hutsell SQ, Griffith JD, Sancar A.
J Biol Chem. 2004 Sep 17;279(38):39289-95. Epub 2004 Jun 28.
PMID 15226314
 
Claspin and Chk1 regulate replication fork stability by different mechanisms.
Scorah J, McGowan CH.
Cell Cycle. 2009 Apr 1;8(7):1036-43. Epub 2009 Apr 2.
PMID 19270516
 
ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage.
Sorensen CS, Syljuasen RG, Lukas J, Bartek J.
Cell Cycle. 2004 Jul;3(7):941-5. Epub 2004 Jul 13.
PMID 15190204
 
Multiple functions of the S-phase checkpoint mediator.
Tanaka K.
Biosci Biotechnol Biochem. 2010;74(12):2367-73. Epub 2010 Dec 7. (REVIEW)
PMID 21150122
 
Evaluation of claspin as a proliferation marker in human cancer and normal tissues.
Tsimaratou K, Kletsas D, Kastrinakis NG, Tsantoulis PK, Evangelou K, Sideridou M, Liontos M, Poulias I, Venere M, Salmas M, Kittas C, Halazonetis TD, Gorgoulis VG.
J Pathol. 2007 Feb;211(3):331-9.
PMID 17152083
 
The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor /progesterone receptor /HER-2 breast carcinomas.
Verlinden L, Vanden Bempt I, Eelen G, Drijkoningen M, Verlinden I, Marchal K, De Wolf-Peeters C, Christiaens MR, Michiels L, Bouillon R, Verstuyf A.
Cancer Res. 2007 Jul 15;67(14):6574-81.
PMID 17638866
 
Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin.
Zhang J, Song YH, Brannigan BW, Wahrer DC, Schiripo TA, Harris PL, Haserlat SM, Ulkus LE, Shannon KM, Garber JE, Freedman ML, Henderson BE, Zou L, Sgroi DC, Haber DA, Bell DW.
Mol Cancer Res. 2009 Sep;7(9):1510-6. doi: 10.1158/1541-7786.MCR-09-0033. Epub 2009 Sep 8.
PMID 19737971
 

Citation

This paper should be referenced as such :
Mannini, L
CLSPN (claspin)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(4):237-239.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CLSPNID40105ch1p34.html


External links

Nomenclature
HGNC (Hugo)CLSPN   19715
Cards
AtlasCLSPNID40105ch1p34
Entrez_Gene (NCBI)CLSPN  63967  claspin
Aliases
GeneCards (Weizmann)CLSPN
Ensembl hg19 (Hinxton)ENSG00000092853 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000092853 [Gene_View]  chr1:35732112-35769950 [Contig_View]  CLSPN [Vega]
ICGC DataPortalENSG00000092853
TCGA cBioPortalCLSPN
AceView (NCBI)CLSPN
Genatlas (Paris)CLSPN
WikiGenes63967
SOURCE (Princeton)CLSPN
Genetics Home Reference (NIH)CLSPN
Genomic and cartography
GoldenPath hg38 (UCSC)CLSPN  -     chr1:35732112-35769950 -  1p34.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CLSPN  -     1p34.3   [Description]    (hg19-Feb_2009)
EnsemblCLSPN - 1p34.3 [CytoView hg19]  CLSPN - 1p34.3 [CytoView hg38]
Mapping of homologs : NCBICLSPN [Mapview hg19]  CLSPN [Mapview hg38]
OMIM605434   
Gene and transcription
Genbank (Entrez)AF297866 AK308193 BC018670 BC038991 BC062215
RefSeq transcript (Entrez)NM_001190481 NM_001330490 NM_022111
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CLSPN
Cluster EST : UnigeneHs.175613 [ NCBI ]
CGAP (NCI)Hs.175613
Alternative Splicing GalleryENSG00000092853
Gene ExpressionCLSPN [ NCBI-GEO ]   CLSPN [ EBI - ARRAY_EXPRESS ]   CLSPN [ SEEK ]   CLSPN [ MEM ]
Gene Expression Viewer (FireBrowse)CLSPN [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)63967
GTEX Portal (Tissue expression)CLSPN
Human Protein AtlasENSG00000092853-CLSPN [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9HAW4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9HAW4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9HAW4
Splice isoforms : SwissVarQ9HAW4
PhosPhoSitePlusQ9HAW4
Domains : Interpro (EBI)Claspin   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CLSPN
DMDM Disease mutations63967
Blocks (Seattle)CLSPN
SuperfamilyQ9HAW4
Human Protein Atlas [tissue]ENSG00000092853-CLSPN [tissue]
Peptide AtlasQ9HAW4
HPRD09257
IPIIPI00879588   IPI00748041   IPI00186968   IPI00981321   
Protein Interaction databases
DIP (DOE-UCLA)Q9HAW4
IntAct (EBI)Q9HAW4
FunCoupENSG00000092853
BioGRIDCLSPN
STRING (EMBL)CLSPN
ZODIACCLSPN
Ontologies - Pathways
QuickGOQ9HAW4
Ontology : AmiGODNA damage checkpoint  DNA binding  protein binding  nucleoplasm  nucleoplasm  Golgi apparatus  DNA replication  DNA repair  anaphase-promoting complex binding  protein deubiquitination  peptidyl-serine phosphorylation  G2 DNA damage checkpoint  activation of protein kinase activity  mitotic DNA replication checkpoint  execution phase of apoptosis  
Ontology : EGO-EBIDNA damage checkpoint  DNA binding  protein binding  nucleoplasm  nucleoplasm  Golgi apparatus  DNA replication  DNA repair  anaphase-promoting complex binding  protein deubiquitination  peptidyl-serine phosphorylation  G2 DNA damage checkpoint  activation of protein kinase activity  mitotic DNA replication checkpoint  execution phase of apoptosis  
REACTOMEQ9HAW4 [protein]
REACTOME PathwaysR-HSA-5693607 [pathway]   
NDEx NetworkCLSPN
Atlas of Cancer Signalling NetworkCLSPN
Wikipedia pathwaysCLSPN
Orthology - Evolution
OrthoDB63967
GeneTree (enSembl)ENSG00000092853
Phylogenetic Trees/Animal Genes : TreeFamCLSPN
HOVERGENQ9HAW4
HOGENOMQ9HAW4
Homologs : HomoloGeneCLSPN
Homology/Alignments : Family Browser (UCSC)CLSPN
Gene fusions - Rearrangements
Fusion : MitelmanNIPBL/CLSPN [5p13.2/1p34.3]  [t(1;5)(p34;p13)]  
Fusion: TCGANIPBL 5p13.2 CLSPN 1p34.3 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCLSPN [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CLSPN
dbVarCLSPN
ClinVarCLSPN
1000_GenomesCLSPN 
Exome Variant ServerCLSPN
ExAC (Exome Aggregation Consortium)ENSG00000092853
GNOMAD BrowserENSG00000092853
Genetic variants : HAPMAP63967
Genomic Variants (DGV)CLSPN [DGVbeta]
DECIPHERCLSPN [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCLSPN 
Mutations
ICGC Data PortalCLSPN 
TCGA Data PortalCLSPN 
Broad Tumor PortalCLSPN
OASIS PortalCLSPN [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCLSPN  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCLSPN
intOGen PortalCLSPN
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CLSPN
DgiDB (Drug Gene Interaction Database)CLSPN
DoCM (Curated mutations)CLSPN (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CLSPN (select a term)
intoGenCLSPN
NCG5 (London)CLSPN
Cancer3DCLSPN(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605434   
Orphanet
MedgenCLSPN
Genetic Testing Registry CLSPN
NextProtQ9HAW4 [Medical]
TSGene63967
GENETestsCLSPN
Target ValidationCLSPN
Huge Navigator CLSPN [HugePedia]
snp3D : Map Gene to Disease63967
BioCentury BCIQCLSPN
ClinGenCLSPN
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD63967
Chemical/Pharm GKB GenePA134920757
Clinical trialCLSPN
Miscellaneous
canSAR (ICR)CLSPN (select the gene name)
Probes
Litterature
PubMed68 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCLSPN
EVEXCLSPN
GoPubMedCLSPN
iHOPCLSPN
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:19:13 CEST 2017

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