Homologous DNA Pairing and Strand Exchange

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R-HSA-5693579
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Homo sapiens
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The presynaptic phase of homologous DNA pairing and strand exchange begins with the displacement of RPA from 3'-ssDNA overhangs created by extensive resection of DNA double strand break (DSB) ends. RPA is displaced by the joint action of RAD51 and BRCA2. BRCA2 nucleates RAD51 on 3'-ssDNA overhangs, leading to formation of invasive RAD51 nucleofilaments which are stabilized by the BCDX2 complex (RAD51B:RAD51C:RAD51D:XRCC2). Stable synaptic pairing between recombining DNA molecules involves the invasion of the homologous sister chromatid duplex DNA by the RAD51 nucleofilament and base-pairing between the invading ssDNA and the complementary sister chromatid DNA strand, while the non-complementary strand of the sister chromatid DNA duplex is displaced. This results in the formation of a D-loop structure (Sung et al., 2003). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity and D-loop formation. PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 also interacts with BRCA1, and this interaction fine-tunes the localization of BRCA2 and RAD51 at DNA DSBs (Zhang et al. 2009, Sy et al. 2009). The CX3 complex, composed of RAD51C and XRCC3, binds D-loop structures through interaction with PALB2 and may be involved in the resolution of Holliday junctions (Chun et al. 2013, Park et al. 2014).

While RAD52 promotes formation of invasive RAD51 nucleofilaments in yeast, human BRCA2 performs this function, while human RAD52 regulates single strand annealing (SSA) (reviewed by Ciccia and Elledge 2010).

Literature References
PubMed ID Title Journal Year
19268590 PALB2 links BRCA1 and BRCA2 in the DNA-damage response

Zhang, F, Ma, J, Wu, J, Ye, L, Cai, H, Xia, B, Yu, X

Curr. Biol. 2009
20871616 Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2

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

Nat. Struct. Mol. Biol. 2010
19369211 PALB2 is an integral component of the BRCA complex required for homologous recombination repair

Sy, SM, Huen, MS, Chen, J

Proc Natl Acad Sci U S A 2009
23149936 Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway

Chun, J, Buechelmaier, ES, Powell, SN

Mol. Cell. Biol. 2013
9880493 Human Rad51 protein can form homologous joints in the absence of net strand exchange.

Gupta, RC, Folta-Stogniew, E, Radding, CM

J Biol Chem 1999
12912992 Rad51 recombinase and recombination mediators.

Sung, P, Krejci, L, Van Komen, S, Sehorn, MG

J Biol Chem 2003
17996711 Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement

Wiese, C, Dray, E, Groesser, T, San Filippo, J, Shi, I, Collins, DW, Tsai, MS, Williams, GJ, Rydberg, B, Sung, P, Schild, D

Mol. Cell 2007
20871615 Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination

Buisson, R, Dion-Côté, AM, Coulombe, Y, Launay, H, Cai, H, Stasiak, AZ, Stasiak, A, Xia, B, Masson, JY

Nat. Struct. Mol. Biol. 2010
20965415 The DNA damage response: making it safe to play with knives

Ciccia, A, Elledge, SJ

Mol. Cell 2010
24141787 Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair

Park, JY, Singh, TR, Nassar, N, Zhang, F, Freund, M, Hanenberg, H, Meetei, AR, Andreassen, PR

Oncogene 2014
17996710 RAD51AP1 is a structure-specific DNA binding protein that stimulates joint molecule formation during RAD51-mediated homologous recombination

Modesti, M, Budzowska, M, Baldeyron, C, Demmers, JA, Ghirlando, R, Kanaar, R

Mol. Cell 2007
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