RAD51 binds BRCA2 at resected DNA DSBs

Stable Identifier
R-HSA-5693561
Type
Reaction
Species
Homo sapiens
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BRCA2 and RAD51 interact directly through the highly conserved BRC repeats in BRCA2 (Venkitaraman 2002). CHEK1-mediated phosphorylation of BRCA2 (at threonine residue T3387) and RAD51 (at threonine residue T309) modulates their binding (Sorensen et al. 2005, Bahassi et al. 2008). One BRCA2 can bind up to six RAD51 molecules, thus playing an important role in RAD51 nucleation at the dsDNA-ssDNA junction created by resection of DNA double-strand breaks (DSBs) (Liu et al. 2010, Thorslund et al. 2010, Jensen et al. 2010). After the nucleation step, additional RAD51 molecules bind the ssDNA and multimerize, forming RAD51 nucleoprotein filaments (Yang et al. 2005). BRCA2-mediated RAD51 loading displaces the RPA complex from 3' overhanging ssDNA at DSBs (Liu et al. 2010, Jensen et al. 2010), possibly with other RPA-bound proteins, such as ATR:ATRIP and complexes involved in ATR catalytic activation.

BRCA2-binding partner SEM1 (DSS1) directly facilitates RPA release from ssDNA and its replacement with RAD51 (Zhao et al. 2015).

The interaction with DNA is critical for BRCA2 function, and the protein contains two different DNA binding regions. The amino-terminal DNA-binding domain (NTD) (residue 267-350) consists of a zinc finger-poly(adenosine diphosphate-ribose) polymerase (PARP)-like domain and binds to different DNA structures (ssDNA, dsDNA, tailed DNA, and gapped DNA) with similar affinity (von Nicolai et al. 2016). The carboxy-terminal DNA-binding domain CTD (residue 2,474-3,190) is significantly more complex with three OB-folds and an apical 3 bundle helix on top of a tower domain preceded by a helical domain (Yang et al. 2002). The proposed breast and ovarian cancer cluster regions (BCCR and OCCR) overlap with the CTD (Rebbeck et al. 2015, Gayther et al. 1997). Several common pathogenic mutations (ClinVar database) and loss-of-function mutations are found in this region including K2630A, K2630D, D2723H.

Literature References
PubMed ID Title Journal Year
20729858 The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA

West, SC, Lekomtsev, S, Compton, SA, McIlwraith, MJ, Petronczki, M, Thorslund, T, Griffith, JD

Nat. Struct. Mol. Biol. 2010
11832208 Cancer susceptibility and the functions of BRCA1 and BRCA2

Venkitaraman, AR

Cell 2002
18317453 The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

Ovesen, JL, Riesenberg, AL, Bahassi, EM, Stambrook, PJ, Hasty, PE, Bernstein, WZ

Oncogene 2008
15703751 The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction

Holloman, WK, Li, Q, Pavletich, NP, Fan, J, Yang, H

Nature 2005
15665856 The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair

Lundin, C, Bartek, J, Dziegielewski, J, Helleday, T, Hansen, LT, Sørensen, CS, Syljuåsen, RG

Nat. Cell Biol. 2005
26145171 Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Jimenez-Sainz, J, Lu, L, Zhao, W, Vaithiyalingam, S, Fontenay, GV, Kwon, Y, Maranon, DG, San Filippo, J, Chazin, WJ, Wiese, C, Leung, SG, Jensen, RB, Sung, P

Mol Cell 2015
20729832 Purified human BRCA2 stimulates RAD51-mediated recombination

Carreira, A, Jensen, RB, Kowalczykowski, SC

Nature 2010
20729859 Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA

Heyer, WD, Doty, T, Gibson, B, Liu, J

Nat. Struct. Mol. Biol. 2010
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