Ku70
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]
| 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:
Reference
- ^ a b c GRCh38: Ensembl release 89: ENSG00000196419 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022471 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c "Entrez Gene: XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku autoantigen, 70kDa)".
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- ^ Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, Guerin A, Ayub M (decembar 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, Haché RJ (maj 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.
- ^ 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.
- ^ Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen DJ, Boothman DA (maj 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.
- ^ Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA (maj 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.
- ^ 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.
- ^ 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.
- ^ Ko L, Cardona GR, Chin WW (maj 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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 (maj 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
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