Ku70 jest protein koji je kod ljudi kodiran genom XRCC6sa hromosoma 22.[5][6]

Ku70
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1JEQ, 1JEY, 1JJR, 3RZX

Identifikatori
AliasiXRCC6
Vanjski ID-jeviOMIM: 152690 MGI: 95606 HomoloGene: 37483 GeneCards: XRCC6
Lokacija gena (čovjek)
Hromosom 22 (čovjek)
Hrom.Hromosom 22 (čovjek)[1]
Hromosom 22 (čovjek)
Genomska lokacija za Ku70
Genomska lokacija za Ku70
Bend22q13.2Početak41,621,163 bp[1]
Kraj41,664,048 bp[1]
Lokacija gena (miš)
Hromosom 15 (miš)
Hrom.Hromosom 15 (miš)[2]
Hromosom 15 (miš)
Genomska lokacija za Ku70
Genomska lokacija za Ku70
Bend15 E1|15 38.33 cMPočetak81,872,036 bp[2]
Kraj81,924,286 bp[2]
Ontologija gena
Molekularna funkcija nucleotide binding
double-stranded telomeric DNA binding
telomeric DNA binding
GO:0008026 helicase activity
5'-deoxyribose-5-phosphate lyase activity
GO:0004003 DNA helicase activity
protein C-terminus binding
catalytic activity
GO:0001948, GO:0016582 vezivanje za proteine
lyase activity
hydrolase activity
ATP binding
vezivanje sa DNK
double-stranded DNA binding
oštećeno vezivanje sa DNK
vezivanje sa RNK
cyclin binding
GO:0032403 protein-containing complex binding
Ćelijska komponenta citosol
nuclear telomere cap complex
membrana
transcription regulator complex
hromosom
nukleoplazma
nonhomologous end joining complex
jedro
Ku70:Ku80 complex
citoplazma
extracellular region
secretory granule lumen
ficolin-1-rich granule lumen
protein-DNA complex
Jedarce
GO:0009327 makromolekulani kompleks
Biološki proces double-strand break repair via classical nonhomologous end joining
protein heterotetramerization
GO:0009373 regulation of transcription, DNA-templated
regulation of smooth muscle cell proliferation
transcription, DNA-templated
cellular response to DNA damage stimulus
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
DNA ligation
establishment of integrated proviral latency
metabolizam
GO:0045996 negative regulation of transcription, DNA-templated
double-strand break repair via nonhomologous end joining
telomere maintenance
positive regulation of type I interferon production
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
DNA duplex unwinding
GO:0100026 Popravka DNK
cellular hyperosmotic salinity response
brain development
DNA recombination
neutrophil degranulation
cellular response to gamma radiation
cellular response to X-ray
positive regulation of protein kinase activity
activation of innate immune response
immune system process
Urođeni imunski sistem
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_001469
NM_001288976
NM_001288977
NM_001288978

NM_010247

RefSeq (bjelančevina)
NP_001275905
NP_001275906
NP_001275907
NP_001460
NP_001275905.1

NP_001460.1

NP_034377

Lokacija (UCSC)Chr 22: 41.62 – 41.66 MbChr 15: 81.87 – 81.92 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 609 aminokiselina, a molekulska težina 69.843 Da. [5]

1020304050
MSGWESYYKTEGDEEAEEEQEENLEASGDYKYSGRDSLIFLVDASKAMFE
SQSEDELTPFDMSIQCIQSVYISKIISSDRDLLAVVFYGTEKDKNSVNFK
NIYVLQELDNPGAKRILELDQFKGQQGQKRFQDMMGHGSDYSLSEVLWVC
ANLFSDVQFKMSHKRIMLFTNEDNPHGNDSAKASRARTKAGDLRDTGIFL
DLMHLKKPGGFDISLFYRDIISIAEDEDLRVHFEESSKLEDLLRKVRAKE
TRKRALSRLKLKLNKDIVISVGIYNLVQKALKPPPIKLYRETNEPVKTKT
RTFNTSTGGLLLPSDTKRSQIYGSRQIILEKEETEELKRFDDPGLMLMGF
KPLVLLKKHHYLRPSLFVYPEESLVIGSSTLFSALLIKCLEKEVAALCRY
TPRRNIPPYFVALVPQEEELDDQKIQVTPPGFQLVFLPFADDKRKMPFTE
KIMATPEQVGKMKAIVEKLRFTYRSDSFENPVLQQHFRNLEALALDLMEP
EQAVDLTLPKVEAMNKRLGSLVDEFKELVYPPDYNPEGKVTKRKHDNEGS
GSKRPKVEYSEEELKTHISKGTLGKFTVPMLKEACRAYGLKSGLKKQELL
EALTKHFQD

Funkcija

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Ku70 i Ku80 zajeno čine Ku heterodimer, koji se vezuje za krajeve dvolančanog prekida DNK i potreban je za put popravka DNK nehomolognim spajanjem krajevaa (NHEJ). Također potreban je za V(D)J rekombinaciju, koja koristi NHEJ put za promoviranje raznolikosti antigena u imunskom sistemu sisara.

Osim svoje uloge u NHEJ, Ku je također potreban za održavanje dužine telomere i utišavanje subtelomernih gena.[7]

Ku je prvobitno identificiran kada je otkriveno da pacijenti sa sistemskim eritemskim lupusom imaju visok nivo autoantitijela na protein.[5]

Starenje

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Mišje embrionske matične ćelije sa homozigotnim Ku70 mutacijama, odnosno Ku70–/– ćelije , imaju značajno povećanu osetljivost na ionizirajuće zračenje u poređenju sa heterozigotnim Ku70+/– ili divljim tipom Ku70 +/+ embrionskih matičnih ćelija.[8] Mutantni miševi s nedostatkom Ku70 imaju rano starenje.[9] Koristeći nekoliko specifičnih kriterija starenja, otkriveno je da mutantni miševi pokazuju iste znakove starenja kao kontrolni miševi, ali u znatno ranijoj hronološkoj dobi. Ovi rezultati sugeriraju da smanjena sposobnost popravljanja dvostrukih lanaca DNK uzrokuje rano starenje i da divlji tip gena Ku70 ima važnu ulogu u osiguranju dugovječnosti.[10]

Klinički značaj

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Mutacija ovog gena je opisana u skupu od 24 porodice sa autizmom.[11] Iako ovo sugeriše da ovaj gen može imati ulogu u razvoju autizma, potrebno je dalje istraživanje.

Nomenklatura

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Ku70 se pominje sa nekoliko imena uključujući:

  • Lupus Ku autoantigeni protein p70
  • Podjedinica 1 ATP-ovisne DNK-helikaze 2
  • Rendgenski popravak koji dopunjuje defektnu popravku u ćelijama kineskog hrčka 6
  • Rendgenski popravak unakrsnog komplementarnog 6 (XRCC6)

Interakcije

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Pokazalo se da Ku70 reaguje sa:

Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000196419 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022471 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c "Entrez Gene: XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku autoantigen, 70kDa)".
  6. ^ Pace P, Mosedale G, Hodskinson MR, Rosado IV, Sivasubramaniam M, Patel KJ (Jul 2010). "Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway". Science. 329 (5988): 219–23. Bibcode:2010Sci...329..219P. doi:10.1126/science.1192277. PMID 20538911. S2CID 206527645.
  7. ^ Boulton SJ, Jackson SP (Mar 1998). "Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing". The EMBO Journal. 17 (6): 1819–28. doi:10.1093/emboj/17.6.1819. PMC 1170529. PMID 9501103.
  8. ^ Gu Y, Jin S, Gao Y, Weaver DT, Alt FW (Jul 1997). "Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination". Proceedings of the National Academy of Sciences of the United States of America. 94 (15): 8076–81. Bibcode:1997PNAS...94.8076G. doi:10.1073/pnas.94.15.8076. PMC 21559. PMID 9223317.
  9. ^ Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (Dec 2007). "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Molecular and Cellular Biology. 27 (23): 8205–14. doi:10.1128/MCB.00785-07. PMC 2169178. PMID 17875923.
  10. ^ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 Arhivirano 25. 10. 2014. na Wayback Machine ISBN 978-1604565812
  11. ^ Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, Guerin A, Ayub M (December 2019). "Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism". Journal of Human Genetics. 65 (3): 287–296. doi:10.1038/s10038-019-0707-0. PMID 31827253. S2CID 209312195.
  12. ^ Song K, Jung Y, Jung D, Lee I (Mar 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–7. doi:10.1074/jbc.M008779200. PMID 11112778.
  13. ^ Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y (Aug 2003). "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". The Journal of Biological Chemistry. 278 (32): 29940–7. doi:10.1074/jbc.M301765200. PMID 12756247.
  14. ^ a b c Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, Berger SL (Mar 1998). "Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex". Molecular and Cellular Biology. 18 (3): 1349–58. doi:10.1128/mcb.18.3.1349. PMC 108848. PMID 9488450.
  15. ^ Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, Haché RJ (May 2001). "The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase". The Journal of Biological Chemistry. 276 (20): 16848–56. doi:10.1074/jbc.M100768200. PMID 11279128.
  16. ^ Gell D, Jackson SP (Sep 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Research. 27 (17): 3494–502. doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239.
  17. ^ Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen DJ, Boothman DA (May 1999). "Isolation of Ku70-binding proteins (KUBs)". Nucleic Acids Research. 27 (10): 2165–74. doi:10.1093/nar/27.10.2165. PMC 148436. PMID 10219089.
  18. ^ Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA (May 1999). "The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit" (PDF). Molecular and Cellular Biology. 19 (5): 3267–77. doi:10.1128/mcb.19.5.3267. PMC 84121. PMID 10207052.
  19. ^ a b Song K, Jung D, Jung Y, Lee SG, Lee I (Sep 2000). "Interaction of human Ku70 with TRF2". FEBS Letters. 481 (1): 81–5. doi:10.1016/S0014-5793(00)01958-X. PMID 10984620.
  20. ^ Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (Oct 1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nature Genetics. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516. S2CID 13443404.
  21. ^ Ko L, Cardona GR, Chin WW (May 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6212–7. Bibcode:2000PNAS...97.6212K. doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.
  22. ^ Ko L, Chin WW (Mar 2003). "Nuclear receptor coactivator thyroid hormone receptor-binding protein (TRBP) interacts with and stimulates its associated DNA-dependent protein kinase". The Journal of Biological Chemistry. 278 (13): 11471–9. doi:10.1074/jbc.M209723200. PMID 12519782.
  23. ^ Grandvaux N, Grizot S, Vignais PV, Dagher MC (Feb 1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". Journal of Cell Science. 112 (4): 503–13. doi:10.1242/jcs.112.4.503. PMID 9914162.
  24. ^ Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (Oct 2002). "A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein". The Journal of Biological Chemistry. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID 12171929.
  25. ^ Balajee AS, Geard CR (Mar 2001). "Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells". Nucleic Acids Research. 29 (6): 1341–51. doi:10.1093/nar/29.6.1341. PMC 29758. PMID 11239001.
  26. ^ Romero F, Multon MC, Ramos-Morales F, Domínguez A, Bernal JA, Pintor-Toro JA, Tortolero M (Mar 2001). "Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase". Nucleic Acids Research. 29 (6): 1300–7. doi:10.1093/nar/29.6.1300. PMC 29753. PMID 11238996.
  27. ^ Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y (Mar 1999). "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". The EMBO Journal. 18 (5): 1397–406. doi:10.1093/emboj/18.5.1397. PMC 1171229. PMID 10064605.
  28. ^ Chai W, Ford LP, Lenertz L, Wright WE, Shay JW (Dec 2002). "Human Ku70/80 associates physically with telomerase through interaction with hTERT". The Journal of Biological Chemistry. 277 (49): 47242–7. doi:10.1074/jbc.M208542200. PMID 12377759.
  29. ^ Romero F, Dargemont C, Pozo F, Reeves WH, Camonis J, Gisselbrecht S, Fischer S (Jan 1996). "p95vav associates with the nuclear protein Ku-70". Molecular and Cellular Biology. 16 (1): 37–44. doi:10.1128/mcb.16.1.37. PMC 230976. PMID 8524317.
  30. ^ Karmakar P, Snowden CM, Ramsden DA, Bohr VA (Aug 2002). "Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus". Nucleic Acids Research. 30 (16): 3583–91. doi:10.1093/nar/gkf482. PMC 134248. PMID 12177300.
  31. ^ Li B, Comai L (Sep 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". The Journal of Biological Chemistry. 275 (37): 28349–52. doi:10.1074/jbc.C000289200. PMID 10880505.

Dopunska literatura

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Vanjski linkovi

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  • PDBe-KB provides an overview of all the structure information available in the PDB for Human X-ray repair cross-complementing protein 6