PALB2

PALB2
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2W18, 3EU7
Identifikatori
Aliasi	PALB2
Vanjski ID-jevi	OMIM: 610355 MGI: 3040695 HomoloGene: 11652 GeneCards: PALB2
Lokacija gena (čovjek)
Hrom.	Hromosom 16 (čovjek)
Kraj	23,641,310 bp
Lokacija gena (miš)
Hrom.	Hromosom 7 (miš)
Kraj	121,732,208 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• nukleoplazma; • jedro;
Biološki proces	• animal organ morphogenesis; • somitogenesis; • post-anal tail morphogenesis; • cellular response to DNA damage stimulus; • DNA recombination; • mesoderm development; • negative regulation of apoptotic process; • in utero embryonic development; • multicellular organism growth; • embryonic organ development; • inner cell mass cell proliferation; • GO:0100026 Popravka DNK; • double-strand break repair via homologous recombination;
	Izvori:Amigo / QuickGO
Ortolozi
	79728
	233826
	ENSG00000083093
	ENSMUSG00000044702
	Q86YC2
	Q3U0P1
	NM_024675
NM_001081238; NM_001289842; NM_001289843; NM_001289844; NM_001289845;
	NM_172744
	NP_078951
	NP_001074707; NP_001276771; NP_001276772; NP_001276773; NP_001276774
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

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

Dužina polipeptidnog lanca je 1.186 aminokiselina, a molekulska težina 131.295 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
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

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

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]

Mejoza

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

Reference

^ ^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

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

Q86YC2
PALB2 Interest Group Arhivirano 12. 1. 2016. na Wayback Machine – research consortium

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000083093 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000044702 - 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.

[entrez-5] "Entrez Gene: PALB2 partner and localizer of BRCA2".

[pmid16793542-6] 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.

[pmid17200672-7] 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.

[pmid20484397-8] 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.

[pmid19633289-9] 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-10] 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.

[pmid21088254-11] 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.

[pmid12239151-12] 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.

[pmid24998779-13] 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-14] 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.

[Buisson_2010-15] 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.

[pmid18794107-16] 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.

[nejm2014-17] 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_2009-18] 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-19] "Ambry Genetics".

[Myriad_Genetics-20] "Myriad Genetics". Arhivirano s originala, 25. 3. 2012. Pristupljeno 21. 2. 2013.

[pmid28594745-21] 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.

[pmid30174725-22] 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.

[pmid31841383-23] 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.

[pmid25016020-24] 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.

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