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]
Clinical significance[]
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[]
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.
^ Jump up to: abXia 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. PMID17200672. S2CID36491877.
^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. PMID21466974.
^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. PMID28594745. S2CID28223281.
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. PMID17200671. S2CID10326242.
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. PMID17200672. S2CID36491877.
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. PMID17287723. S2CID4340489.