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.
West, SC, Lekomtsev, S, Compton, SA, McIlwraith, MJ, Petronczki, M, Thorslund, T, Griffith, JD
Venkitaraman, AR
Ovesen, JL, Riesenberg, AL, Bahassi, EM, Stambrook, PJ, Hasty, PE, Bernstein, WZ
Holloman, WK, Li, Q, Pavletich, NP, Fan, J, Yang, H
Lundin, C, Bartek, J, Dziegielewski, J, Helleday, T, Hansen, LT, Sørensen, CS, Syljuåsen, RG
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
Carreira, A, Jensen, RB, Kowalczykowski, SC
Heyer, WD, Doty, T, Gibson, B, Liu, J
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