PALB2
Partner i lokalizator BRCA2, znan i kao PALB2 ili FANCN, jest protein koji je kod ljudi kodiran genom PALB2 sa hromosoma 16.[5][6][7]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 1.186 aminokiselina, a molekulska težina 131.295 Da.[5]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MDEPPGKPLS | CEEKEKLKEK | LAFLKREYSK | TLARLQRAQR | AEKIKHSIKK | ||||
TVEEQDCLSQ | QDLSPQLKHS | EPKNKICVYD | KLHIKTHLDE | ETGEKTSITL | ||||
DVGPESFNPG | DGPGGLPIQR | TDDTQEHFPH | RVSDPSGEQK | QKLPSRRKKQ | ||||
QKRTFISQER | DCVFGTDSLR | LSGKRLKEQE | EISSKNPARS | PVTEIRTHLL | ||||
SLKSELPDSP | EPVTEINEDS | VLIPPTAQPE | KGVDTFLRRP | NFTRATTVPL | ||||
QTLSDSGSSQ | HLEHIPPKGS | SELTTHDLKN | IRFTSPVSLE | AQGKKMTVST | ||||
DNLLVNKAIS | KSGQLPTSSN | LEANISCSLN | ELTYNNLPAN | ENQNLKEQNQ | ||||
TEKSLKSPSD | TLDGRNENLQ | ESEILSQPKS | LSLEATSPLS | AEKHSCTVPE | ||||
GLLFPAEYYV | RTTRSMSNCQ | RKVAVEAVIQ | SHLDVKKKGF | KNKNKDASKN | ||||
LNLSNEETDQ | SEIRMSGTCT | GQPSSRTSQK | LLSLTKVSSP | AGPTEDNDLS | ||||
RKAVAQAPGR | RYTGKRKSAC | TPASDHCEPL | LPTSSLSIVN | RSKEEVTSHK | ||||
YQHEKLFIQV | KGKKSRHQKE | DSLSWSNSAY | LSLDDDAFTA | PFHRDGMLSL | ||||
KQLLSFLSIT | DFQLPDEDFG | PLKLEKVKSC | SEKPVEPFES | KMFGERHLKE | ||||
GSCIFPEELS | PKRMDTEMED | LEEDLIVLPG | KSHPKRPNSQ | SQHTKTGLSS | ||||
SILLYTPLNT | VAPDDNDRPT | TDMCSPAFPI | LGTTPAFGPQ | GSYEKASTEV | ||||
AGRTCCTPQL | AHLKDSVCLA | SDTKQFDSSG | SPAKPHTTLQ | VSGRQGQPTC | ||||
DCDSVPPGTP | PPIESFTFKE | NQLCRNTCQE | LHKHSVEQTE | TAELPASDSI | ||||
NPGNLQLVSE | LKNPSGSCSV | DVSAMFWERA | GCKEPCIITA | CEDVVSLWKA | ||||
LDAWQWEKLY | TWHFAEVPVL | QIVPVPDVYN | LVCVALGNLE | IREIRALFCS | ||||
SDDESEKQVL | LKSGNIKAVL | GLTKRRLVSS | SGTLSDQQVE | VMTFAEDGGG | ||||
KENQFLMPPE | ETILTFAEVQ | GMQEALLGTT | IMNNIVIWNL | KTGQLLKKMH | ||||
IDDSYQASVC | HKAYSEMGLL | FIVLSHPCAK | ESESLRSPVF | QLIVINPKTT | ||||
LSVGVMLYCL | PPGQAGRFLE | GDVKDHCAAA | ILTSGTIAIW | DLLLGQCTAL | ||||
LPPVSDQHWS | FVKWSGTDSH | LLAGQKDGNI | FVYHYS |
Funkcija
[uredi | uredi izvor]![](http://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/PALB2_en.svg/400px-PALB2_en.svg.png)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/dc/Homologous_recombinational_repair_of_DNA_double-strand_damage.jpg/300px-Homologous_recombinational_repair_of_DNA_double-strand_damage.jpg)
Ovaj gen kodira protein koji funkcioniše u održavanju genoma (popravak dvostrukog lanca). Ovaj protein se veže i kolokalizira s proteinom ranog početka raka dojke 2 (BRCA2) u jedarnim žarištima i vjerovatno omogućava stabilnu unutarjedarnu lokalizaciju i akumulaciju BRCA2.[5] PALB2 vezuje jedan lanac DNK i direktno stupa u interakciju s rekombinazom RAD51, kako bi stimulirao invaziju lanaca, vitalni korak homologne rekombinacije,[15] PALB2 može funkcionirati sinergijski s himerom BRCA2 vanom piccolo ili piBRCA2), kako bi dalje promovirao invaziju niti.[15]
Klinički značaj
[uredi | uredi izvor]Varijante gena PALB2 povezane su sa povećanim rizikom od razvoja raka dojke [16] veličine slične onoj povezanoj s mutacijama BRCA2 [17] a ćelije sa nedostatkom PALB2 osjetljive su na PARP inhibitore.[15]
Naučnici iz Sol Goldman Centra za istraživanje raka pankreasa u Johns Hopkinsu nedavno su identificirali PALB2 kao gen osjetljivosti na porodični rak pankreasa. Ovo je utrlo put za razvoj novog genskog testa za porodice u kojima se rak pankreasa javlja u više članova porodice.[18] Ambry je Testove za PALB2 razvili su Ambry Genetics [19] i Myriad Genetics[20] koji su sada dostupni.
Profilaksna mastektomija treba biti razmotrena za žene koje su imale rak dojke i mutaciju PALB2.[21][22]
Bialelne mutacije u PALB2 (također poznate kao FANCN), slične bialelnim mutacijama BRCA2, uzrokuju Fanconijevu anemiju.[7]
Mutacije ovog gena povezane su s povećanim rizikom od raka jajnika, dojke i gušterače.[23]
Mutirani PALB2 muški miševi imaju smanjenu plodnost.[24] Čini se da je ova smanjena plodnost posljedica trošenja zametnih ćelija koje je rezultat kombinacije nepopravljenih prekida DNK tokom mejoze i defektne sinapse hromosoma X i Y. Čini se da je funkcija popravka oštećenja DNK putedm homologne rekombinacije tokom mejoze, posebno prekida dvostrukih lanaca. Interakcija PALB2-BRCA1 je vjerovatno važna za popravku takvih oštećenja tokom mejoze muškaraca.
Također pogledajte
[uredi | uredi izvor]Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000083093 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000044702 - 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: PALB2 partner and localizer of BRCA2".
- ^ Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. (juni 2006). "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Molecular Cell. 22 (6): 719–29. doi:10.1016/j.molcel.2006.05.022. PMID 16793542.
- ^ a b Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, et al. (februar 2007). "Fanconi anemia is associated with a defect in the BRCA2 partner PALB2". Nature Genetics. 39 (2): 159–61. doi:10.1038/ng1942. PMID 17200672. S2CID 36491877.
- ^ D'Andrea AD (maj 2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". The New England Journal of Medicine. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.
- ^ Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (septembar 2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". The Journal of Biological Chemistry. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.
- ^ Castillo P, Bogliolo M, Surralles J (maj 2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair. 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
- ^ Stolz A, Ertych N, Bastians H (februar 2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clinical Cancer Research. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
- ^ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (oktobar 2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151. S2CID 11001855.
- ^ Park JY, Zhang F, Andreassen PR (august 2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.
- ^ Chun J, Buechelmaier ES, Powell SN (januar 2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Molecular and Cellular Biology. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
- ^ a b c Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, et al. (oktobar 2010). "Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination". Nature Structural & Molecular Biology. 17 (10): 1247–54. doi:10.1038/nsmb.1915. PMC 4094107. PMID 20871615.
- ^ Chen P, Liang J, Wang Z, Zhou X, Chen L, Li M, et al. (septembar 2008). "Association of common PALB2 polymorphisms with breast cancer risk: a case-control study". Clinical Cancer Research. 14 (18): 5931–7. doi:10.1158/1078-0432.CCR-08-0429. PMID 18794107.
- ^ Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, et al. (august 2014). "Breast-cancer risk in families with mutations in PALB2". The New England Journal of Medicine. 371 (6): 497–506. doi:10.1056/NEJMoa1400382. PMC 4157599. PMID 25099575.
- ^ Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. (april 2009). "Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene". Science. 324 (5924): 217. Bibcode:2009Sci...324..217J. doi:10.1126/science.1171202. PMC 2684332. PMID 19264984.
- ^ "Ambry Genetics".
- ^ "Myriad Genetics". Arhivirano s originala, 25. 3. 2012. Pristupljeno 21. 2. 2013.
- ^ Wright FC, Look Hong NJ, Quan ML, Beyfuss K, Temple S, Covelli A, et al. (februar 2018). "Indications for Contralateral Prophylactic Mastectomy: A Consensus Statement Using Modified Delphi Methodology". Annals of Surgery. 267 (2): 271–279. doi:10.1097/SLA.0000000000002309. PMID 28594745. S2CID 28223281.
- ^ Song CV, Teo SH, Taib NA, Yip CH (2018). "BRCA, TP53 and PALB2: a literature review". ecancermedicalscience. 12: 863. doi:10.3332/ecancer.2018.863. PMC 6113980. PMID 30174725.
- ^ Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, et al. (decembar 2019). "PALB2 Pathogenic Variants: An International Study of 524 Families". Journal of Clinical Oncology. 38 (7): 674–685. doi:10.1200/JCO.19.01907. PMC 7049229. PMID 31841383.
- ^ Simhadri S, Peterson S, Patel DS, Huo Y, Cai H, Bowman-Colin C, et al. (august 2014). "Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice". The Journal of Biological Chemistry. 289 (35): 24617–29. doi:10.1074/jbc.M114.566141. PMC 4148885. PMID 25016020.
Dopunska literatura
[uredi | uredi izvor]- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, et al. (august 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (januar 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. (juni 2006). "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Molecular Cell. 22 (6): 719–29. doi:10.1016/j.molcel.2006.05.022. PMID 16793542.
- Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, et al. (februar 2007). "PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene". Nature Genetics. 39 (2): 165–7. doi:10.1038/ng1959. PMC 2871593. PMID 17200668.
- Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. (februar 2007). "Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer". Nature Genetics. 39 (2): 162–4. doi:10.1038/ng1947. PMID 17200671. S2CID 10326242.
- Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, et al. (februar 2007). "Fanconi anemia is associated with a defect in the BRCA2 partner PALB2". Nature Genetics. 39 (2): 159–61. doi:10.1038/ng1942. PMID 17200672. S2CID 36491877.
- Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, et al. (mart 2007). "A recurrent mutation in PALB2 in Finnish cancer families". Nature. 446 (7133): 316–9. Bibcode:2007Natur.446..316E. doi:10.1038/nature05609. PMID 17287723. S2CID 4340489.
- Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, et al. (april 2007). "Analysis of PALB2/FANCN-associated breast cancer families". Proceedings of the National Academy of Sciences of the United States of America. 104 (16): 6788–93. Bibcode:2007PNAS..104.6788T. doi:10.1073/pnas.0701724104. PMC 1871863. PMID 17420451.
- Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH (septembar 2009). "Structural basis for recruitment of BRCA2 by PALB2". EMBO Reports. 10 (9): 990–6. doi:10.1038/embor.2009.126. PMC 2750052. PMID 19609323.
Vanjski linkovi
[uredi | uredi izvor]- Q86YC2
- PALB2 Interest Group Arhivirano 12. 1. 2016. na Wayback Machine – research consortium