PALB2

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PALB2
PALB2 BRCA2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PALB2, FANCN, PNCA3, partner and localizer of BRCA2
External IDs MGI: 3040695 HomoloGene: 11652 GeneCards: 79728
RNA expression pattern
PBB GE PALB2 219530 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_024675

RefSeq (protein)

NP_078951.2

NP_001074707.1
NP_001276771.1
NP_001276772.1
NP_001276773.1
NP_001276774.1

Location (UCSC) Chr 16: 23.6 – 23.64 Mb Chr 7: 122.11 – 122.13 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.[3][4][5]

Function[edit]

Characterized domaines of PALB2
Recombinational repair of DNA double-strand damage - some key steps. ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).[6] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[7] ATM activates (phosphorylates) CHEK2 and FANCD2[8] CHEK2 phosphorylates BRCA1.[9] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[10] The PALB2 protein acts as a hub,[11] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[12] RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

This gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.[3] PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion, a vital step of homologous recombination,[13] (see Figure "Homologous recombinational repair of DNA double-strand damage"). PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[13]

Clinical significance[edit]

Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [14] of magnitude similar to that associated with BRCA2 mutations [15] and PALB2-deficient cells are sensitive to PARP inhibitors.[13]

PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer by scientists at the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. This has paved for the way for developing a new gene test for families where pancreatic cancer occurs in multiple family members.[16] Tests for PALB2 have been developed by Ambry Genetics [17] and Myriad Genetics[18] that are now available. The PALB2 Interest Group (PALB2.org) is an international consortium of scientists and clinicians who coordinate research into this gene.

Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[5]

Meiosis[edit]

PALB2 mutant male mice have reduced fertility.[19] This reduced fertility appears to be due to germ cell attrition resulting from a combination of unrepaired DNA breaks during meiosis and defective synapsis of the X and Y chromosomes. The function of homologous recombination during meiosis appears to be repair of DNA damages, particularly double-strand breaks[20] (also see Origin and function of meiosis). The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis.

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b "Entrez Gene: PALB2 partner and localizer of BRCA2". 
  4. ^ Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM (June 2006). "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Mol. Cell. 22 (6): 719–29. doi:10.1016/j.molcel.2006.05.022. PMID 16793542. 
  5. ^ a b Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP (February 2007). "Fanconi anemia is associated with a defect in the BRCA2 partner PALB2". Nat. Genet. 39 (2): 159–61. doi:10.1038/ng1942. PMID 17200672. 
  6. ^ D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698free to read. PMID 20484397. 
  7. ^ Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957free to read. PMID 19633289. 
  8. ^ Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974. 
  9. ^ Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254. 
  10. ^ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (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. 
  11. ^ Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126free to read. PMID 24998779. 
  12. ^ Chun J, Buechelmaier ES, Powell SN (2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112free to read. PMID 23149936. 
  13. ^ a b c Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, Stasiak A, Xia B, Masson JY (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. PMID 20871615. 
  14. ^ Chen P, Liang J, Wang Z, Zhou X, Chen L, Li M, Xie D, Hu Z, Shen H, Wang H (September 2008). "Association of common PALB2 polymorphisms with breast cancer risk: a case-control study". Clin. Cancer Res. 14 (18): 5931–7. doi:10.1158/1078-0432.CCR-08-0429. PMID 18794107. 
  15. ^ Antoniou A, et al. (August 7, 2014). "Breast-Cancer Risk in Families with Mutations in PALB2". N Engl J Med 2014. 371: 497–506. doi:10.1056/NEJMoa1400382. 
  16. ^ Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP (2009). "Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene.". Science. 324 (5924): 217. doi:10.1126/science.1171202. PMC 2684332free to read. PMID 19264984. 
  17. ^ "Ambry Genetics". 
  18. ^ "Myriad Genetics". 
  19. ^ Simhadri S, Peterson S, Patel DS, Huo Y, Cai H, Bowman-Colin C, Miller S, Ludwig T, Ganesan S, Bhaumik M, Bunting SF, Jasin M, Xia B (2014). "Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice". J. Biol. Chem. 289 (35): 24617–29. doi:10.1074/jbc.M114.566141. PMC 4148885free to read. PMID 25016020. 
  20. ^ Bernstein H and Bernstein C (2013). Evolutionary Origin and Adaptive Function of Meiosis. In Meiosis: Bernstein C and Bernstein H, editors. ISBN 978-953-51-1197-9, InTech, http://www.intechopen.com/books/meiosis/evolutionary-origin-and-adaptive-function-of-meiosis

Further reading[edit]