Resolution of D-loop Structures through Holliday Junction Intermediates

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D-loops generated after strand invasion and DNA repair synthesis during homologous recombination repair (HRR) can be resolved through Holliday junction intermediates.

A D-loop can be cleaved by the complex of MUS81 and EME1 (MUS81:EME1) or MUS81 and EME2 (MUS81:EME2) and resolved without the formation of double Holliday junctions, generating cross-over products. All steps involved in this process have not been elucidated (Osman et al. 2003, Schwartz et al. 2012, Pepe and West 2014).

Alternatively, double Holliday junctions can be created by ligation of crossed-strand intermediates. Double Holliday junctions can then be resolved through the action of the BLM helicase complex known as BTRR (BLM:TOP3A:RMI1:RMI2) (Wan et al. 2013, Bocquet et al. 2014). BLM-mediated resolution of Holliday junction intermediates prevents sister chromatid exchange (SCE) between mitotic chromosomes and generates non-crossover products. SPIDR enables recruitment of the BTTR complex to the ionizing radiation-induced foci. The complex of FIGNL1 and FIRRM, which, through FIGNL1, simultaneously interacts with SPIDR (Yuan and Chen 2013) and RAD51 (Yuan and Chen 2013, Fernandes et al. 2018), may facilitate the function of SPIDR in promoting the no cross-over route of homologous recombination repair. Mitotic SCE can result in the loss-of-heterozygosity (LOH), which can make the cell homozygous for deleterious recessive mutations (e.g. in tumor suppressor genes) (Wu and Hickson 2003). Double Holliday junctions can also be resolved by cleavage, mediated by GEN1 or the SLX-MUS complex (composed of SLX1A:SLX4 heterodimer and a heterodimer of MUS81 and EME1 or, possibly, EME2). The resolvase activity of GEN1 and SLX-MUS predominantly results in crossover products, with SCE (Fekairi et al. 2009, Wyatt et al. 2013, Sarbajna et al. 2014).

Literature References
PubMed ID Title Journal Year
14527420 Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis

Doe, CL, Osman, F, Whitby, MC, Dixon, J

Mol. Cell 2003
23509288 Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair

Chen, H, Huang, J, Liu, T, Han, J, Dong, S, Wan, L, Xie, F

Proc. Natl. Acad. Sci. U.S.A. 2013
24371268 Substrate specificity of the MUS81-EME2 structure selective endonuclease

West, SC, Pepe, A

Nucleic Acids Res. 2014
24076221 Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells

West, SC, Matos, J, Sarbajna, S, Wyatt, HD

Mol. Cell 2013
24831703 Roles of SLX1-SLX4, MUS81-EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

West, SC, Sarbajna, S, Davies, D

Genes Dev. 2014
14685245 The Bloom's syndrome helicase suppresses crossing over during homologous recombination

Hickson, ID, Wu, L

Nature 2003
19596236 Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases

Yates, JR, Coulon, S, Ruse, C, Fekairi, S, Russell, P, McGowan, CH, Tissier, A, Gaillard, PH, Taylor, ER, Dong, MQ, Chahwan, C, Fuchs, RP, Scaglione, S

Cell 2009
24509834 Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase III? and RMI1

Larsen, NB, Hickson, ID, Bizard, AH, Bunker, RD, Abdulrahman, W, Thomä, NH, Cejka, P, Faty, M, Kowalczykowski, SC, Bocquet, N, Cavadini, S

Nat. Struct. Mol. Biol. 2014
22645308 Mus81-Mms4 functions as a single heterodimer to cleave nicked intermediates in recombinational DNA repair

Heyer, WD, Wright, WD, Stahlberg, H, Schwartz, EK, Evans, JE, Ehmsen, KT

Mol. Cell. Biol. 2012
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