PALB2
Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.[5][6][7]
Function
[edit]
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.[5] PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion, a vital step of homologous recombination,[15] PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[15]
Clinical significance
[edit]Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [16] of magnitude similar to that associated with BRCA2 mutations [17] and PALB2-deficient cells are sensitive to PARP inhibitors.[15]
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.[18] Tests for PALB2 have been developed by Ambry Genetics [19] and Myriad Genetics[20] that are now available.
Prophylactic mastectomy should be considered for women that had breast cancer and a PALB2 mutation.[21][22]
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[7]
Mutations in this gene have been associated with an increased risk of ovarian, breast and pancreatic cancer.[23]
Meiosis
[edit]PALB2 mutant male mice have reduced fertility.[24] 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 (also see Origin and function of meiosis).[citation needed] The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis.
See also
[edit]References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000083093 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000044702 – Ensembl, May 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 "Entrez Gene: PALB2 partner and localizer of BRCA2".
- ^ Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. (June 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. (February 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 (May 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 (September 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 (May 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 (February 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 (October 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 (January 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. (October 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. (September 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. S2CID 18701211.
- ^ 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". Archived from the original on 2012-03-25. Retrieved 2013-02-21.
- ^ Wright FC, Look Hong NJ, Quan ML, Beyfuss K, Temple S, Covelli A, et al. (February 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. (December 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.
Further reading
[edit]- 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. (January 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. (June 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. (February 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. (February 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. (February 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. (March 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 (September 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.
External links
[edit]- Overview of all the structural information available in the PDB for UniProt: Q86YC2 (Partner and localizer of BRCA2) at the PDBe-KB.
- PALB2 Interest Group Archived 2016-01-12 at the Wayback Machine – research consortium