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http://dx.doi.org/10.14348/molcells.2014.2346

Tumour Suppressor Mechanisms in the Control of Chromosome Stability: Insights from BRCA2  

Venkitaraman, Ashok R. (University of Cambridge, Medical Research Council Cancer Unit, Hutchison, MRC Research Centre)
Publication Information
Molecules and Cells / v.37, no.2, 2014 , pp. 95-99 More about this Journal
Abstract
Cancer is unique amongst human diseases in that its cellular manifestations arise and evolve through the acquisition of somatic alterations in the genome. In particular, instability in the number and structure of chromosomes is a near-universal feature of the genomic alterations associated with epithelial cancers, and is triggered by the inactivation of tumour suppressor mechanisms that preserve chromosome integrity in normal cells. The nature of these mechanisms, and how their inactivation promotes carcinogenesis, remains enigmatic. I will review recent work from our laboratory on the tumour suppressor BRCA2 that addresses these issues, focusing on new insights into cancer pathogenesis and therapy that are emerging from improved understanding of the molecular basis of chromosomal instability in BRCA2-deficient cancer cells.
Keywords
BRCA2; cancer; chromosomal aberrations; DNA repair; genome instability; mitosis;
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1 Caldas, C., and Kern, S.E. (1995). K-ras mutation and pancreatic adenocarcinoma. Int. J. Pancreatol. 18, 1-6.
2 Ayoub, N., Rajendra, E., Su, X., Jeyasekharan, A.D., Mahen, R., and Venkitaraman, A.R. (2009). The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry. Curr. Biol. 19, 1075-1085.   DOI   ScienceOn
3 Breast Cancer Linkage Consortium (1999). The breast cancer linkage consortium: cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310-1316.   DOI
4 Bryant, H.E., Schultz, N., Thomas, H.D., Parker, K.M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N.J., and Helleday, T. (2005). Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917.   DOI   ScienceOn
5 Cancer Genome Atlas Consortium (2011). Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615.   DOI   ScienceOn
6 Carreira, A., Hilario, J., Amitani, I., Baskin, R.J., Shivji, M.K., Venkitaraman, A.R., and Kowalczykowski, S.C. (2009). The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136, 1032-1043.   DOI   ScienceOn
7 Friedman, L.S., Thistlethwaite, F.C., Patel, K.J., Yu, V.P., Lee, H., Venkitaraman, A.R., Abel, K.J., Carlton, M.B., Hunter, S.M., Colledge, W.H., et al. (1998). Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res. 58, 1338-1343.
8 Couch, F.J., Johnson, M.R., Rabe, K.G., Brune, K., de Andrade, M., Goggins, M., Rothenmund, H., Gallinger, S., Klein, A., Petersen, G.M., et al. (2007). The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 16, 342-346.   DOI   ScienceOn
9 Daniels, M.J., Wang, Y., Lee, M., and Venkitaraman, A.R. (2004). Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876-879.   DOI   ScienceOn
10 Farmer, H., McCabe, N., Lord, C.J., Tutt, A.N., Johnson, D.A., Richardson, T.B., Santarosa, M., Dillon, K.J., Hickson, I., Knights C., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921.   DOI   ScienceOn
11 Gretarsdottir, S., Thorlacius, S., Valgardsdottir, R., Gudlaugsdottir, S., Sigurdsson, S., Steinarsdottir, M., Jonasson, J.G., Anamthawat- Jonsson, K., and Eyfjord, J.E. (1998). BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability. Cancer Res. 58, 859-862.
12 Hahn, S.A., Greenhalf, B., Ellis, I., Sina-Frey, M., Rieder, H., Korte, B., Gerdes, B., Kress, R., Ziegler, A., Raeburn, J.A., et al. (2003). BRCA2 germline mutations in familial pancreatic carcinoma. J. Natl. Cancer Inst. 95, 214-221.   DOI   ScienceOn
13 Hezel, A.F., Kimmelman, A.C., Stanger, B.Z., Bardeesy, N., and Depinho, R.A. (2006). Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218-1249.   DOI   ScienceOn
14 Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., and Berns, A. (2001). Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418-425.   DOI   ScienceOn
15 Hruban, R., Pitman, M., and Klimstra, D.S. (2007). Tumors of the Pancreas, AFIP ATLAS of Tumour Pathology, Series IV, (American Registry of Pathology).
16 Lee, M., Daniels, M.J., Garnett, M.J., and Venkitaraman, A.R. (2011). A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor. Oncogene 30, 3360-3369.   DOI   ScienceOn
17 Jeyasekharan, A.D., Liu, Y., Hattori, H., Pisupati, V., Jonsdottir, A.B., Rajendra, E., Lee, M., Sundaramoorthy, E., Schlachter, S., Kaminski, C.F., et al. (2013). A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat. Struct. Mol. Biol. 20, 1191-1198.   DOI   ScienceOn
18 King, T.A., Li, W., Brogi, E., Yee, C.J., Gemignani, M.L., Olvera, N., Levine, D.A., Norton, L., Robson, M.E., Offit, K., et al. (2007). Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann. Surg. Oncol. 14, 2510-2518.   DOI
19 Lomonosov, M., Anand, S., Sangrithi, M., Davies, R., and Venkitaraman, A.R. (2003). Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes Dev. 17, 3017-3022.   DOI   ScienceOn
20 Maitra, A., and Hruban, R.H. (2008). Pancreatic cancer. Annu. Rev. Pathol. 3, 157-188.   DOI   ScienceOn
21 Menzel, T., Nahse-Kumpf, V., Kousholt, A.N., Klein, D.K., Lund-Andersen, C., Lees, M., Johansen, J.V., Syljuasen, R.G., and Sorensen, C.S. (2011). A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance. EMBO Rep. 12, 705-712.   DOI   ScienceOn
22 Parkin, D.M., Bray, F.I., and Devesa, S.S. (2001). Cancer burden in the year 2000. The global picture. Eur. J. Cancer 37, S4-66.
23 Mikaelsdottir, E.K., Valgeirsdottir, S., Eyfjord, J.E., and Rafnar, T. (2004). The Icelandic founder mutation BRCA2 999del5: analysis of expression. Breast Cancer Res. 6, R284-290.   DOI   ScienceOn
24 Redston, M.S., Caldas, C., Seymour, A.B., Hruban, R.H., da Costa, L., Yeo, C.J., and Kern, S.E. (1994). p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 54, 3025-3033.
25 Mondal, G., Rowley, M., Guidugli, L., Wu, J., Pankratz, V.S., and Couch, F.J. (2012). BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev. Cell 23, 137-152.   DOI   ScienceOn
26 Patel, K.J., Yu, V.P., Lee, H., Corcoran, A., Thistlethwaite, F.C., Evans, M.J., Colledge, W.H., Friedman, L.S., Ponder, B.A., and Venkitaraman, A.R. (1998). Involvement of Brca2 in DNA repair. Mol. Cell 1, 347-357.   DOI   ScienceOn
27 Schlacher, K., Christ, N., Siaud, N., Egashira, A., Wu, H., and Jasin, M. (2011). Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529-542.   DOI   ScienceOn
28 Shivji, M.K., Mukund, S.R., Rajendra, E., Chen, S., Short, J.M., Savill, J., Klenerman, D., and Venkitaraman, A.R. (2009). The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange. Proc. Natl. Acad. Sci. USA 106, 13254-13259.   DOI   ScienceOn
29 Thompson, D., and Easton, D.F. (2002). Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94, 1358-1365.   DOI   ScienceOn
30 Skoulidis, F., Cassidy, L.D., Pisupati, V., Jonasson, J.G., Bjarnason, H., Eyfjord, J.E., Karreth, F.A., Lim, M., Barber, L.M., Clatworthy, S.A., et al. (2010). Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell 18, 499-509.   DOI   ScienceOn
31 Venkitaraman, A.R. (2009). Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol. 4, 461-487.   DOI   ScienceOn
32 Tirkkonen, M., Johannsson, O., Agnarsson, B.A., Olsson, H., Ingvarsson, S., Karhu, R., Tanner, M., Isola, J., Barkardottir, R.B., Borg, A., et al. (1997). Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 57, 1222-1227.
33 Tutt, A.N., van Oostrom, C.T., Ross, G.M., van Steeg, H., and Ashworth, A. (2002). Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation. EMBO Rep. 3, 255-260.   DOI   ScienceOn
34 Venkitaraman, A.R. (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171-182.   DOI   ScienceOn
35 West, S.C. (2003). Molecular views of recombination proteins and their control. Nat. Rev. Mol. Cell Biol. 4, 435-445.
36 Willems-Jones, A., Kavanagh, L., Clouston, D., Bolton, D., kCon-Fab Investigators, Fox, S., and Thorne, H. (2012). High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer. BJU Int. 110, E1181-E1186.   DOI   ScienceOn
37 Wooster, R., Neuhausen, S.L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., et al. (1994). Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265, 2088-2090.   DOI
38 Xu, X., Weaver, Z., Linke, S.P., Li, C., Gotay, J., Wang, X.W., Harris, C.C., Ried, T., and Deng, C.X. (1999). Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 3, 389-395.   DOI   ScienceOn
39 Yu, V.P., Koehler, M., Steinlein, C., Schmid, M., Hanakahi, L.A., van Gool, A.J., West, S.C., and Venkitaraman, A.R. (2000). Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14, 1400-1406.
40 Choi, E., Park, P.G., Lee, H.O., Lee, Y.K., Kang, G.H., Lee, J.W., Han, W., Lee, H.C., Noh, D.Y., Lekomtsev, S., et al. (2012). BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation. Dev. Cell 22, 295-308   DOI   ScienceOn