PALB2

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).[8] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[9] ATM activates (phosphorylates) CHEK2 and FANCD2[10] CHEK2 phosphorylates BRCA1.[11] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[12] The PALB2 protein acts as a hub,[13] 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.[14] 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.[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]

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]

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). The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis.

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

• 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