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Pathogenesis and therapy of BRCA2-deficient cancers

 

Structural and biochemical studies of BRCA2 in  RAD51-dependent homologous recombination. 

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A. Two modules in the BRC repeats of BRCA2 mediate structural and functional interactions with the RAD51 recombination enzyme (see Rajendra & Venkitaraman, Nuc Acids Res (2010)). B. A schematic illustration summarizing the functions of BRCA2 in the assembly of RAD51 filaments on damaged DNA (see Venkitaraman, Ann Rev Pathol (2009)). C. BRC repeats delay dsDNA capture (top panel) coincident with joint molecule formation (bottom panel) in a reconstituted RAD51-mediated DNA recombination reaction (see Shivji et al Proc Nat Acad Sci USA (2009)). D. Opposing actions of the BRC repeats stabilize ssDNA-RAD51 binding whilst inhibiting dsDNA-RAD51 capture to coordinate RAD51-mediated strand exchange (see Shivji et al Proc Nat Acad Sci USA (2009)).
Instability in the number and structure of chromosomes is a hallmark of cancer. We seek to understand the tumour suppressive mechanisms that preserve chromosome integrity during DNA replication, repair and mitosis, and to exploit this understanding in new approaches for cancer therapy that can be applied in the clinic. 

We have used the familial cancer syndrome associated with germline mutations in theBRCA2 tumour suppressor gene as a powerful model system in which to explore the origins of chromosomal instability during epithelial carcinogenesis, and its contribution to cancer development.

We were the first to show in 1998 that BRCA2 inactivation leads to spontaneous chromosomal instability during cell division, and have since made a series of discoveries that identify the essential functions of BRCA2 in preserving chromosome structure through functions in regulating DNA recombination mediated by the recombinase RAD51, and chromosome number, through functions in mitosis. Our work demonstrating an essential role for BRCA2 in stabilizing stalled DNA replication forks provides a mechanistic basis for new approaches to targeted therapy being tested in the clinic.

We have recently developed a novel model for tissue-specific carcinogenesis associated with BRCA2 inactivation, providing new insights into the pathogenesis and therapy of these tumours.

Analysis of the pathogenesis and therapy of BRCA2-mutant cancers using genetics and molecular cell biology.

Selected references are cited below.

Selected Publications:

Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Venkitaraman, A.R. Science (2014) 343(6178):1470-5.

A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Jeyasekharan, A.D., Liu, Y., Hattori, H., Pisupati, V., Jonsdottir, A.B., Rajendra, E., Lee, M., Sundaramoorthy, E., Schlachter, S., Kaminski, C., Rosenfeld, Y., Sato, K., Savill, J., Ayoub, N.& Venkitaraman, A.R. Nature Str Mol Biol. (2013). 20, 1191-8.

A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor. Lee M, Daniels MJ, Garnett MJ, Venkitaraman AR. Oncogene. 2011 Mar 14. [Epub ahead of print]

Modifying chromatin architecture during the response to DNA breakage.Venkitaraman AR. Crit Rev Biochem Mol Biol. 2010 Feb;45(1):2-13.

Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Skoulidis F, Cassidy LD, Pisupati V, Jonasson JG, Bjarnason H, Eyfjord JE, Karreth FA, Lim M, Barber LM, Clatworthy SA, Davies SE, Olive KP, Tuveson DA, Venkitaraman AR. Cancer Cell. 2010 Nov 16;18(5):499-509. 

Two modules in the BRC repeats of BRCA2 mediate structural and functional interactions with the RAD51 recombinase. Rajendra E, Venkitaraman AR. Nucleic Acids Res. 2010 Jan;38(1):82-96.

DNA damage regulates the mobility of Brca2 within the nucleoplasm of living cells.Jeyasekharan AD, Ayoub N, Mahen R, Ries J, Esposito A, Rajendra E, Hattori H, Kulkarni RP, Venkitaraman AR. Proc Natl Acad Sci USA. 2010 Dec 14;107(50):21937-42.

The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC. Cell. 2009 Mar 20;136(6):1032-43.

The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry. Ayoub N, Rajendra E, Su X, Jeyasekharan AD, Mahen R, Venkitaraman AR.Curr Biol. 2009 Jul 14;19(13):1075-85.

The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange. Shivji MK, Mukund SR, Rajendra E, Chen S, Short JM, Savill J, Klenerman D, Venkitaraman AR. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13254-9. 

Targeting the molecular defect in BRCA-deficient tumors for cancer therapy.Venkitaraman AR. Cancer Cell. 2009 Aug 4;16(2):89-90.

Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment.Venkitaraman AR. Annu Rev Pathol. 2009;4:461-87.

HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR. Nature. 2008 May 29;453(7195):682-6. 

A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange. Shivji MK, Davies OR, Savill JM, Bates DL, Pellegrini L, Venkitaraman AR. Nucleic Acids Res. 2006;34(14):4000-11. 

Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Science. 2004 Oct 29;306(5697):876-9. 

Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2. Yu DS, Sonoda E, Takeda S, Huang CL, Pellegrini L, Blundell TL, Venkitaraman AR. Mol Cell. 2003 Oct;12(4):1029-41.

Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Lomonosov M, Anand S, Sangrithi M, Davies R, Venkitaraman AR. Genes Dev. 2003 Dec 15;17(24):3017-22.

Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL, Venkitaraman AR. Nature. 2002 Nov 21;420(6913):287-93. 

Cancer susceptibility and the functions of BRCA1 and BRCA2. Venkitaraman AR. Cell. 2002 Jan 25;108(2):171-82. 

Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Yu VP, Koehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ, West SC, Venkitaraman AR. Genes Dev. 2000 Jun 1;14(11):1400-6.

Involvement of Brca2 in DNA repair. Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR.Mol Cell. 1998 Feb;1(3):347-57.