Protein Bloomovog sindroma

BLM
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 2KV2, 2MH9, 2RRD, 3WE2, 3WE3, 4CDG, 4CGZ, 4O3M
Identifikatori
Aliasi	BLM
Vanjski ID-jevi	OMIM: 604610 MGI: 1328362 HomoloGene: 47902 GeneCards: BLM
EC broj	5.6.2.4
Lokacija gena (čovjek) Hrom. Hromosom 15 (čovjek) Bend 15q26.1 Početak 90,717,346 bp Kraj 90,816,166 bp
Lokacija gena (miš) Hrom. Hromosom 7 (miš) Bend 7 D2|7 45.65 cM Početak 80,104,481 bp Kraj 80,184,867 bp
Ontologija gena Molekularna funkcija • ATP-dependent DNA/DNA annealing activity • nucleotide binding • GO:0008026 helicase activity • GO:0004003 DNA helicase activity • bubble DNA binding • p53 binding • G-quadruplex DNA binding • single-stranded DNA binding • GO:0102490, GO:0102491, GO:0102489, GO:0102488, GO:0102487, GO:0102486, GO:0102485 hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides • ATPase activity • GO:0001948, GO:0016582 vezivanje za proteine • catalytic activity • nucleic acid binding • GO:1990163 four-way junction helicase activity • hydrolase activity • ATP binding • GO:0043140 3'-5' DNA helicase activity • four-way junction DNA binding • Y-form DNA binding • forked DNA-dependent helicase activity • telomeric D-loop binding • telomeric G-quadruplex DNA binding • 8-hydroxy-2'-deoxyguanosine DNA binding • vezivanje sa DNK • ATP-dependent activity, acting on DNA • vezivanje iona cinka • protein homodimerization activity • vezivanje iona metala Ćelijska komponenta • PML body • nuclear matrix • intracellular anatomical structure • nukleoplazma • lateralni element • Telomera • nuclear chromosome • Jedarce • jedro • citoplazma • citosol • replication fork • hromosom • pronucleus Biološki proces • DNA recombination • regulation of cyclin-dependent protein serine/threonine kinase activity • replication fork protection • DNA double-strand break processing • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • negative regulation of cell division • cellular response to camptothecin • cell metabolism • protein complex oligomerization • replication fork processing • negative regulation of DNA recombination • cellular response to ionizing radiation • mitotic G2 DNA damage checkpoint signaling • response to X-ray • cellular response to hydroxyurea • GO:0100026 Popravka DNK • double-strand break repair via homologous recombination • telomeric D-loop disassembly • Replikacija DNK • t-circle formation • DNA duplex unwinding • G-quadruplex DNA unwinding • protein homooligomerization • regulation of DNA-dependent DNA replication • cellular response to DNA damage stimulus • resolution of meiotic recombination intermediates • DNA synthesis involved in DNA repair • strand displacement • double-strand break repair via nonhomologous end joining • meiotic DNA double-strand break processing involved in reciprocal meiotic recombination • negative regulation of apoptotic process • double-strand break repair via synthesis-dependent strand annealing • negative regulation of mitotic recombination • alpha-beta T cell differentiation • positive regulation of alpha-beta T cell proliferation • meiotic chromosome separation • negative regulation of thymocyte apoptotic process • resolution of recombination intermediates • negative regulation of double-strand break repair via single-strand annealing • positive regulation of double-strand break repair via homologous recombination • regulation of signal transduction by p53 class mediator • telomere maintenance • DNA unwinding involved in DNA replication Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	641	12144
Ensembl	ENSG00000197299	ENSMUSG00000030528
UniProt	P54132	O88700
RefSeq (mRNK)	NM_000057 NM_001287246 NM_001287247 NM_001287248	NM_001042527 NM_007550
RefSeq (bjelančevina)	NP_000048 NP_001274175 NP_001274176 NP_001274177 NP_001274177.1	NP_001035992 NP_031576
Lokacija (UCSC)	Chr 15: 90.72 – 90.82 Mb	Chr 7: 80.1 – 80.18 Mb
PubMed pretraga
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Protein Bloomovog sindroma je protein koji je kod ljudi kodiran genom BLM sa hromosoma 15, koji nije eksprimiran u Bloomovom sindromu.

Genski proizvod Bloomovog sindroma povezan je sa RecQ podskupom DNK helikaze koji sadrži DExH kutiju i ima aktivnosti DNK stimulirane ATPaze i ATP-ovisne DNK helikaze. Mutacije koje uzrokuju Bloomov sindrom deletiraju ili mijenjaju motive helikaze i mogu onemogućiti aktivnost 3' → 5' helikaze. Normalni protein može djelovati na suzbijanje neodgovarajuće homologne rekombinacije.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 1.417 aminokiselina, a molekulska težina 159.000 Da.

• 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
MAAVPQNNLQ		EQLERHSART		LNNKLSLSKP		KFSGFTFKKK		TSSDNNVSVT
NVSVAKTPVL		RNKDVNVTED		FSFSEPLPNT		TNQQRVKDFF		KNAPAGQETQ
RGGSKSLLPD		FLQTPKEVVC		TTQNTPTVKK		SRDTALKKLE		FSSSPDSLST
INDWDDMDDF		DTSETSKSFV		TPPQSHFVRV		STAQKSKKGK		RNFFKAQLYT
TNTVKTDLPP		PSSESEQIDL		TEEQKDDSEW		LSSDVICIDD		GPIAEVHINE
DAQESDSLKT		HLEDERDNSE		KKKNLEEAEL		HSTEKVPCIE		FDDDDYDTDF
VPPSPEEIIS		ASSSSSKCLS		TLKDLDTSDR		KEDVLSTSKD		LLSKPEKMSM
QELNPETSTD		CDARQISLQQ		QLIHVMEHIC		KLIDTIPDDK		LKLLDCGNEL
LQQRNIRRKL		LTEVDFNKSD		ASLLGSLWRY		RPDSLDGPME		GDSCPTGNSM
KELNFSHLPS		NSVSPGDCLL		TTTLGKTGFS		ATRKNLFERP		LFNTHLQKSF
VSSNWAETPR		LGKKNESSYF		PGNVLTSTAV		KDQNKHTASI		NDLERETQPS
YDIDNFDIDD		FDDDDDWEDI		MHNLAASKSS		TAAYQPIKEG		RPIKSVSERL
SSAKTDCLPV		SSTAQNINFS		ESIQNYTDKS		AQNLASRNLK		HERFQSLSFP
HTKEMMKIFH		KKFGLHNFRT		NQLEAINAAL		LGEDCFILMP		TGGGKSLCYQ
LPACVSPGVT		VVISPLRSLI		VDQVQKLTSL		DIPATYLTGD		KTDSEATNIY
LQLSKKDPII		KLLYVTPEKI		CASNRLISTL		ENLYERKLLA		RFVIDEAHCV
SQWGHDFRQD		YKRMNMLRQK		FPSVPVMALT		ATANPRVQKD		ILTQLKILRP
QVFSMSFNRH		NLKYYVLPKK		PKKVAFDCLE		WIRKHHPYDS		GIIYCLSRRE
CDTMADTLQR		DGLAALAYHA		GLSDSARDEV		QQKWINQDGC		QVICATIAFG
MGIDKPDVRF		VIHASLPKSV		EGYYQESGRA		GRDGEISHCL		LFYTYHDVTR
LKRLIMMEKD		GNHHTRETHF		NNLYSMVHYC		ENITECRRIQ		LLAYFGENGF
NPDFCKKHPD		VSCDNCCKTK		DYKTRDVTDD		VKSIVRFVQE		HSSSQGMRNI
KHVGPSGRFT		MNMLVDIFLG		SKSAKIQSGI		FGKGSAYSRH		NAERLFKKLI
LDKILDEDLY		INANDQAIAY		VMLGNKAQTV		LNGNLKVDFM		ETENSSSVKK
QKALVAKVSQ		REEMVKKCLG		ELTEVCKSLG		KVFGVHYFNI		FNTVTLKKLA
ESLSSDPEVL		LQIDGVTEDK		LEKYGAEVIS		VLQKYSEWTS		PAEDSSPGIS
LSSSRGPGRS		AAEELDEEIP		VSSHYFASKT		RNERKRKKMP		ASQRSKRRKT
ASSGSKAKGG		SATCRKISSK		TKSSSIIGSS		SASHTSQATS		GANSKLGIMA
PPKPINRPFL		KPSYAFS

Mejoza

Model mejotske rekombinacije, iniciran prekidom ili prazninom dvostrukog lanca, nakon čega slijedi uparivanje s homolognim hromosomom i invazija lanca kako bi se pokrenuo proces rekombinacijske popravke. Popravka jaza može dovesti do krosing-overa (CO) ili nekrosinga (NCO) bočnih regija. Smatra se da se rekombinacija CO javlja pomoću modela dvostrukpg Hollidayevog spoja (DHJ), ilustrovanog na desnoj strani, iznad. Smatra se da se NCO rekombinanti javljaju prvenstveno po modelu udvajanja ovisnog o lancima od sinteze (SDSA), koji je ilustrovan lijevo, gore. Čini se da je većina događaja rekombinacije tipa SDSA.

Rekombinacija tokom mejoze je često inicirana prekidom dvostrukog lanca DNK (DSB). Tokom rekombinacije, dijelovi DNK na 5' krajevima prekida se odsijecaju u procesu koji se zove resekcija. U koraku invazije lanca koji slijedi, nadvišena 3' kraj slomljenog molekula DNK tada "napada" DNK homolognog hromosoma koji nije slomljen. Nakon invazije lanca, daljnji slijed događaja može pratiti bilo koji od dva glavna puta koji vode do krosingovera (CO) ili bez njega (NCO) rekombinanta (pogledajte Genetička rekombinacija i donji dio slike u ovom odjeljku).

Pupajući kvasac Saccharomyces cerevisiae kodira ortolog proteina Bloomovog sindroma (BLM) koji je označen kao Sgs1 (mali supresor rasta 1). Sgs1(BLM) je helikaza koja funkcionira popravkama homolognom rekombinacijom DSB-a. Čini se da je helikaza Sgs1(BLM) centralni regulator većine rekombinacijskih događaja koji se dešavaju tokom mejoza uS. cerevisiae. Tokom normalne mejoze Sgs1(BLM) je odgovoran za usmjeravanje rekombinacije ka alternativnom formiranju ili ranih NCO-a ili Hollidayevih spona zglobnih molekula, pri čemu se potonji kasnije rješavaju kao COs.

U biljci Arabidopsis thaliana, homolozi Sgs1(BLM) helikaze djeluju kao glavne barijere za mejotsko stvaranje CO. Smatra se da ove helikaze istiskuju invazivni lanac, omogućavajući njegovo udvostručavanje s drugim 3'-prepustnim krajem DSB-a, što dovodi do formiranja NCO rekombinantnog procesa postupkom koji se naziva udvostručavanje lanca ovisno o sintezi (SDSA) (vidi Genetička rekombinacija i sliku na ovaj odeljak). Procjenjuje se da je samo oko 4% DSB-a popravljeno rekombinacijom CO, Sequela-Arnaud et al. sugerirajići da su brojevi CO ograničeni zbog dugoročnih troškova rekombinacije CO, odnosno razbijanja povoljnih genetičkih kombinacija alela stvorenih prošlim prirodnim odabiranjem.

Interakcije

Pokazalo se da protein Bloomovog sindroma reaguje sa:

• ATM,
• CHAF1A,
• CHEK1,
• FANCM,
• FEN1,
• H2AFX,
• MLH1
• P53,
• RAD51L3,
• RAD51,
• RPA1,
• TOP3A,
• TP53BP1,
• WRN, i
• XRCC2.

Dopunska literatura

• Woo LL, Onel K, Ellis NA (2007). "The broken genome: genetic and pharmacologic approaches to breaking DNA". Ann. Med. 39 (3): 208–18. doi:10.1080/08035250601167136. PMID 17457718. S2CID 30395226.
• McDaniel LD, Schultz RA (1992). "Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15". Proc. Natl. Acad. Sci. U.S.A. 89 (17): 7968–72. Bibcode:1992PNAS...89.7968M. doi:10.1073/pnas.89.17.7968. PMC 49836. PMID 1518822.
• Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J (1995). "The Bloom's syndrome gene product is homologous to RecQ helicases". Cell. 83 (4): 655–66. doi:10.1016/0092-8674(95)90105-1. PMID 7585968. S2CID 13439128.
• German J, Roe AM, Leppert MF, Ellis NA (1994). "Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1". Proc. Natl. Acad. Sci. U.S.A. 91 (14): 6669–73. Bibcode:1994PNAS...91.6669G. doi:10.1073/pnas.91.14.6669. PMC 44264. PMID 8022833.
• Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guéret M (1998). "Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome". Hum. Mol. Genet. 6 (9): 1427–34. doi:10.1093/hmg/6.9.1427. PMID 9285778.
• Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N (1997). "BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal". Biochem. Biophys. Res. Commun. 240 (2): 348–53. doi:10.1006/bbrc.1997.7648. PMID 9388480.
• Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (2000). "The Bloom's syndrome gene product interacts with topoisomerase III". J. Biol. Chem. 275 (13): 9636–44. doi:10.1074/jbc.275.13.9636. PMID 10734115.
• Yankiwski V, Marciniak RA, Guarente L, Neff NF (2000). "Nuclear structure in normal and Bloom syndrome cells". Proc. Natl. Acad. Sci. U.S.A. 97 (10): 5214–9. Bibcode:2000PNAS...97.5214Y. doi:10.1073/pnas.090525897. PMC 25808. PMID 10779560.
• Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.
• Karow JK, Constantinou A, Li JL, West SC, Hickson ID (2000). "The Bloom's syndrome gene product promotes branch migration of Holliday junctions". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6504–8. Bibcode:2000PNAS...97.6504K. doi:10.1073/pnas.100448097. PMC 18638. PMID 10823897.
• Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (2000). "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". J. Biol. Chem. 275 (31): 23500–8. doi:10.1074/jbc.M001557200. PMID 10825162.
• Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guéret M (2000). "Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase". Oncogene. 19 (23): 2731–8. doi:10.1038/sj.onc.1203595. PMID 10851073.
• Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guéret M (2000). "Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome". Hum. Mutat. 15 (6): 584–5. doi:10.1002/1098-1004(200006)15:6<584::AID-HUMU28>3.0.CO;2-I. PMID 10862105. S2CID 41245824.
• Brosh RM, Karow JK, White EJ, Shaw ND, Hickson ID, Bohr VA (2000). "Potent inhibition of Werner and Bloom helicases by DNA minor groove binding drugs". Nucleic Acids Res. 28 (12): 2420–30. doi:10.1093/nar/28.12.2420. PMC 102731. PMID 10871376.
• Wu L, Davies SL, Levitt NC, Hickson ID (2001). "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. 276 (22): 19375–81. doi:10.1074/jbc.M009471200. PMID 11278509.
• Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J (2001). "The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair". J. Biol. Chem. 276 (32): 30031–5. doi:10.1074/jbc.M009664200. PMID 11325959.
• Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC (2001). "Functional interaction of p53 and BLM DNA helicase in apoptosis". J. Biol. Chem. 276 (35): 32948–55. doi:10.1074/jbc.M103298200. PMID 11399766.
• Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Hum. Mol. Genet. 10 (12): 1287–98. doi:10.1093/hmg/10.12.1287. PMID 11406610.
• Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIα". Nucleic Acids Res. 29 (15): 3172–80. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874.

Vanjski linkovi

• GeneReviews/NCBI/NIH/UW entry on Bloom Syndrome
• Lokacija ljudskog genoma BLM i stranica sa detaljima o genu BLM u UCSC Genome Browseru.
• P54132