Biology:PALB2

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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

Function

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). The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI. ATM activates (phosphorylates) CHEK2 and FANCD2 CHEK2 phosphorylates BRCA1. Ubiquinated FANCD2 complexes with BRCA1 and RAD51. The PALB2 protein acts as a hub, 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. 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. PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion, a vital step of homologous recombination, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.

Clinical significance

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

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. Tests for PALB2 have been developed by Ambry Genetics and Myriad Genetics that are now available.

Prophylactic mastectomy should be considered for women that had breast cancer and a PALB2 mutation.

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

Mutations in this gene have been associated with an increased risk of ovarian, breast and pancreatic cancer.

Meiosis

PALB2 mutant male mice have reduced fertility. 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). The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis.

See also

• Fanconi anemia
• BRCA2
• DNA repair
• Tumor suppressor gene

Further reading

• "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. August 2004. doi:10.1073/pnas.0404720101. PMID 15302935. Bibcode: 2004PNAS..10112130B. 
• "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. January 2006. doi:10.1101/gr.4039406. PMID 16344560. 
• "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Molecular Cell 22 (6): 719–29. June 2006. doi:10.1016/j.molcel.2006.05.022. PMID 16793542. 
• "PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene". Nature Genetics 39 (2): 165–7. February 2007. doi:10.1038/ng1959. PMID 17200668. 
• "Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer". Nature Genetics 39 (2): 162–4. February 2007. doi:10.1038/ng1947. PMID 17200671. 
• "Fanconi anemia is associated with a defect in the BRCA2 partner PALB2". Nature Genetics 39 (2): 159–61. February 2007. doi:10.1038/ng1942. PMID 17200672. 
• "A recurrent mutation in PALB2 in Finnish cancer families". Nature 446 (7133): 316–9. March 2007. doi:10.1038/nature05609. PMID 17287723. Bibcode: 2007Natur.446..316E. 
• "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. April 2007. doi:10.1073/pnas.0701724104. PMID 17420451. Bibcode: 2007PNAS..104.6788T. 
• "Structural basis for recruitment of BRCA2 by PALB2". EMBO Reports 10 (9): 990–6. September 2009. doi:10.1038/embor.2009.126. PMID 19609323. 

External links

• 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 – research consortium