Ku70

Ku70
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1JEQ, 1JEY, 1JJR, 3RZX
Identifikatori
Aliasi	XRCC6
Vanjski ID-jevi	OMIM: 152690 MGI: 95606 HomoloGene: 37483 GeneCards: XRCC6
Lokacija gena (čovjek) Hrom. Hromosom 22 (čovjek)[1] Bend 22q13.2 Početak 41,621,163 bp[1] Kraj 41,664,048 bp[1]
Lokacija gena (miš) Hrom. Hromosom 15 (miš)[2] Bend 15 E1|15 38.33 cM Početak 81,872,036 bp[2] Kraj 81,924,286 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
Vrste	Čovjek	Miš
Entrez	2547	14375
Ensembl	ENSG00000196419	ENSMUSG00000022471
UniProt	P12956	P23475
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 Mb	Chr 15: 81.87 – 81.92 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

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

Aminokiselinska sekvenca

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

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MSGWESYYKT		EGDEEAEEEQ		EENLEASGDY		KYSGRDSLIF		LVDASKAMFE
SQSEDELTPF		DMSIQCIQSV		YISKIISSDR		DLLAVVFYGT		EKDKNSVNFK
NIYVLQELDN		PGAKRILELD		QFKGQQGQKR		FQDMMGHGSD		YSLSEVLWVC
ANLFSDVQFK		MSHKRIMLFT		NEDNPHGNDS		AKASRARTKA		GDLRDTGIFL
DLMHLKKPGG		FDISLFYRDI		ISIAEDEDLR		VHFEESSKLE		DLLRKVRAKE
TRKRALSRLK		LKLNKDIVIS		VGIYNLVQKA		LKPPPIKLYR		ETNEPVKTKT
RTFNTSTGGL		LLPSDTKRSQ		IYGSRQIILE		KEETEELKRF		DDPGLMLMGF
KPLVLLKKHH		YLRPSLFVYP		EESLVIGSST		LFSALLIKCL		EKEVAALCRY
TPRRNIPPYF		VALVPQEEEL		DDQKIQVTPP		GFQLVFLPFA		DDKRKMPFTE
KIMATPEQVG		KMKAIVEKLR		FTYRSDSFEN		PVLQQHFRNL		EALALDLMEP
EQAVDLTLPK		VEAMNKRLGS		LVDEFKELVY		PPDYNPEGKV		TKRKHDNEGS
GSKRPKVEYS		EEELKTHISK		GTLGKFTVPM		LKEACRAYGL		KSGLKKQELL
EALTKHFQD

Funkcija

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

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

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

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

Pokazalo se da Ku70 reaguje sa:

• CBX5,^[12]
• CHEK1,^[13]
• CREBBP,^[14]
• GCN5L2,^[14]
• HOXC4,^[15]
• Ku80,^{[14][16][17][18][19]}
• MRE11A,^[20]
• NCOA6,^[21][22]
• NCF4,^[23]
• PCNA,^[24][25]
• PTTG1,^[26]
• RPA2,^[27]
• TERF2,^[19]
• TERT^[28]
• VAV1,^[29] i
• WRN.^[30][31]

Reference

1. GRCh38: Ensembl release 89: ENSG00000196419 - Ensembl, maj 2017
2. 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. "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. 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. 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

• Smider V, Chu G (Jun 1997). "The end-joining reaction in V(D)J recombination". Seminars in Immunology. 9 (3): 189–97. doi:10.1006/smim.1997.0070. PMID 9200330.
• Featherstone C, Jackson SP (May 1999). "Ku, a DNA repair protein with multiple cellular functions?". Mutation Research. 434 (1): 3–15. doi:10.1016/s0921-8777(99)00006-3. PMID 10377944.
• Koike M (Sep 2002). "Dimerization, translocation and localization of Ku70 and Ku80 proteins". Journal of Radiation Research. 43 (3): 223–36. Bibcode:2002JRadR..43..223K. doi:10.1269/jrr.43.223. PMID 12518983.

Vanjski linkovi

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