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Mechanisms and principles of homology search during recombination

Key Points

  • Homology search is the crucial step during homologous recombination that involves the encounter of two homologous sequences, the constant probing for homology and the final recognition of the homologous site.

  • The mechanism of homology search, which was previously considered to be one of the most enigmatic processes in DNA double-strand break (DSB) repair, is now partially understood owing to several methodological advances.

  • The proposed 'accelerated random search model' suggests that homology search functions by a random probing mechanism that is carried out by the RecA or RAD51 presynaptic nucleoprotein filament in three dimensions. However, the model further suggests that probing is accelerated by engaging multiple contacts of the filament with DNA and by sliding of the filament along DNA.

  • As spatial proximity seems to be a key determinant of efficient homology search, chromatin architecture and nuclear organization have a decisive role during the search process.

  • Mediators of homology search are either proteins or structures that restrict and guide the search to donor sequences, or factors that actively facilitate homology probing in the context of chromatin and histones.

Abstract

Homologous recombination is crucial for genome stability and for genetic exchange. Although our knowledge of the principle steps in recombination and its machinery is well advanced, homology search, the critical step of exploring the genome for homologous sequences to enable recombination, has remained mostly enigmatic. However, recent methodological advances have provided considerable new insights into this fundamental step in recombination that can be integrated into a mechanistic model. These advances emphasize the importance of genomic proximity and nuclear organization for homology search and the critical role of homology search mediators in this process. They also aid our understanding of how homology search might lead to unwanted and potentially disease-promoting recombination events.

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Figure 1: Homology probing in vitro.
Figure 2: Accelerated random search model.

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Acknowledgements

S.J. is supported by the Max Planck Society, Deutsche Forschungsgemeinschaft, Center for Integrated Protein Science Munich, RUBICON EU Network of Excellence, European Research Council (ERC) Advanced Grant and the Louis-Jeantet Foundation. J.R. was supported by a Boehringer Ingelheim Fonds PhD stipend.

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Glossary

Mating-type switching

A process by which yeast cells switch their mating-type through programmed homologous recombination.

Strand exchange

A continuous establishment of base pairing between the recombinase-coated single-stranded DNA (ssDNA), at the DNA double-strand break (DSB), and the complementary strand of the homologous DNA.

Heteroduplex

Double-stranded DNA that consists of two single DNA strands of different origin.

B-DNA

Standard conformation of DNA as it exists in most functional organisms.

Repetitive elements

Genetic elements, such as satellite DNA or retrotransposons, that are present in multiple copies in a genome and/or consist of small repetitive building blocks.

Ectopic homologous recombination

Recombination with a homologous sequence that is located in a genomic location other than the corresponding allele on the sister chromatid or homologous chromosome.

Recombination enhancer

A specific sequence that is present in the genome of the yeast Saccharomyces cerevisiae, which enables the establishment of a large chromosomal loop to facilitate recombination in cells of mating-type a (MATa).

Chromosome conformation capture

A method to analyze the spatial interaction frequency of either selected genomic loci or of loci on a genome-wide level. It is based on the chemical crosslinking of samples, which is followed by their restriction digest and a subsequent ligation procedure.

Displacement loop

(D-loop). A structure in which the two strands of a DNA duplex are separated by the binding of a third strand to one of these strands.

ATP-dependent chromatin remodelling complexes

Protein complexes that use the energy of ATP to reposition nucleosomes, evict histones or incorporate new histone variants.

Structural maintenance of chromosome proteins

(SMC proteins). A conserved ATPase protein family that coordinates many aspects of chromosome organization, for example sister-chromatid cohesion and chromosome condensation in mitosis.

V(D)J recombination

Combination of variable (V), diverse (D) and joining(J) gene segments during a programmed recombination event in lymphoid cells to form diverse immunoglobulins and T cell receptors.

Class switch recombination

Programmed recombination in B lymphocytes to generate different antibody subtypes with the same antigen specificity.

Surface protein gene arrangements

A mechanism that enables some pathogens to evade the host adaptive immune system by altering their immunogenic epitopes (antigenic variation) through recombination-mediated switching between several different surface protein variants.

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Renkawitz, J., Lademann, C. & Jentsch, S. Mechanisms and principles of homology search during recombination. Nat Rev Mol Cell Biol 15, 369–383 (2014). https://doi.org/10.1038/nrm3805

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