2w18

Structural highlights

Disease

PALB2_HUMAN Defects in PALB2 are a cause of susceptibility to breast cancer (BC) [MIM:114480. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=Breast cancer susceptibility is strongly associated with PALB2 truncating mutations. Conversely, rare missense mutations do not strongly influence breast cancer risk (PubMed:22241545). Defects in PALB2 are the cause of Fanconi anemia complementation group N (FANCN) [MIM:610832. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.^[1] Defects in PALB2 are the cause of pancreatic cancer type 3 (PNCA3) [MIM:613348. It is a malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.^[2]

Function

PALB2_HUMAN Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination. Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51. Essential partner of BRCA2 that promotes the localization and stability of BRCA2. Also enables its recombinational repair and checkpoint functions of BRCA2. May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Binds DNA with high affinity for D loop, which comprises single-stranded, double-stranded and branched DNA structures.^{[3] [4] [5] [6] [7]}

References

1. ↑ 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. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007 Feb;39(2):159-61. Epub 2006 Dec 31. PMID:17200672 doi:10.1038/ng1942
2. ↑ 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. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009 Apr 10;324(5924):217. doi: 10.1126/science.1171202. Epub 2009 Mar, 5. PMID:19264984 doi:10.1126/science.1171202
3. ↑ Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006 Jun 23;22(6):719-29. PMID:16793542 doi:10.1016/j.molcel.2006.05.022
4. ↑ Sy SM, Huen MS, Zhu Y, Chen J. PALB2 regulates recombinational repair through chromatin association and oligomerization. J Biol Chem. 2009 Jul 3;284(27):18302-10. doi: 10.1074/jbc.M109.016717. Epub 2009, May 7. PMID:19423707 doi:10.1074/jbc.M109.016717
5. ↑ Sy SM, Huen MS, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60. doi:, 10.1073/pnas.0811159106. Epub 2009 Apr 15. PMID:19369211 doi:10.1073/pnas.0811159106
6. ↑ Buisson R, Dion-Cote AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, Stasiak A, Xia B, Masson JY. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol. 2010 Oct;17(10):1247-54. doi: 10.1038/nsmb.1915. Epub 2010, Sep 26. PMID:20871615 doi:10.1038/nsmb.1915
7. ↑ Dray E, Etchin J, Wiese C, Saro D, Williams GJ, Hammel M, Yu X, Galkin VE, Liu D, Tsai MS, Sy SM, Schild D, Egelman E, Chen J, Sung P. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat Struct Mol Biol. 2010 Oct;17(10):1255-9. doi: 10.1038/nsmb.1916. Epub 2010, Sep 26. PMID:20871616 doi:10.1038/nsmb.1916
8. ↑ Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009 Sep;10(9):990-6. Epub 2009 Jul 17. PMID:19609323 doi:10.1038/embor.2009.126