Homologous recombination (HR) is a universal DNA repair mechanism that faithfully restores genomic integrity following double-strand breaks (DSBs) in DNA.
The details concerning the transfer of information between two interacting homologous sequences have been uncovered. However, little is known about the processes by which the molecules colocalize.
HR takes place efficiently even between homologous sequences located on different chromosomes. Following the creation of a single DSB in a yeast chromosome, a genome-wide search for homology can allow repair by HR in 100% of the cells in less than 2 hours.
A basic model of homology search in which the broken arms randomly search throughout the whole genome for homologous sequences cannot account for the efficiency and the speed at which repair occurs and presents spatial and topological problems.
An alternative possibility is that homologous sequences are already paired before the DSB. However, evidence for such somatic pairing is controversial in many species.
In many organisms, centromeres tend to aggregate in vegetative cells (the Rabl configuration) and telomeres merge in meiotic cells (the 'bouquet' configuration). Such spatial genome organization brings allelic loci closer together and might aid homologous pairing.
During meiosis, homologous chromosomes pair and engage in HR. In some organisms, such as yeast, plants and animals, pairing depends on DSB formation. By contrast, pairing in worms and flies is independent of DSB formation.
In mammalian cells, chromosomes are organized in discrete non-overlapping chromosome territories; here, non-homologous end joining is the preponderant DSB repair mechanism. However, the compartmentalization of the genome is not stringent and HR occurs at significant rates.
In several species, homologous pairing has important functions in genetic and epigenetic processes other than DNA repair.
Decades of research into homologous recombination have unravelled many of the details concerning the transfer of information between two homologous sequences. By contrast, the processes by which the interacting molecules initially colocalize are largely unknown. How can two homologous needles find each other in the genomic haystack? Is homologous pairing the result of a damage-induced homology search, or is it an enduring and general feature of the genomic architecture that facilitates homologous recombination whenever and wherever damage occurs? This Review presents the homologous-pairing enigma, delineates our current understanding of the process and offers guidelines for future research.
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Work on the mechanism of homology search during DSB repair was supported by grants to M.K. from the Israel Science Foundation. We apologize to authors whose work we could not cite owing to space constraints. We would like to thank all members of the Kupiec laboratory for help and encouragement. We are grateful to J. Loidl and A. Strunnikov for providing the images used in Fig. 3.
- Homing endonucleases
A large and universal class of nucleases, usually encoded by mobile genetic elements such as group I introns and inteins, that promote their own dissemination by homologous recombination.
- Integrative transformation
A process by which a linear molecule of DNA is introduced into a cell and is incorporated into its genome.
- High-frequency recombination conjugation
A mechanism by which bacteria can exchange large chromosomal fragments.
- General transduction
A process in which bacterial viruses transfer chromosomal regions between bacteria.
- Heteroduplex DNA
A DNA molecule generated by annealing of complementary single strands derived from different parental duplex molecules. Heteroduplex DNA often contains mismatches.
- Isogenic strains
Strains that are genetically identical, except for a single, or a few, specific trait(s).
A trans effect on gene expression that is conveyed between homologous regulatory regions, such as enhancers or silencers.
- Nucleolar organizing region
A chromosomal segment, rich in ribosomal DNA (rDNA), that has the ability to organize the nucleolus around it.
- X inactivation
The process in which one X chromosome in each cell of the female embryo is inactivated.
- Cis-acting pairing centres
Chromosomal regions that are important for pairing of homologues during meiosis.
- Distributive disjunction
The meiotic segregation of chromosomes that did not engage in recombination.
- Transcription factory
A nuclear subcompartment that is rich in RNA polymerases and transcription factors where dispersed genes gather to become active.
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Barzel, A., Kupiec, M. Finding a match: how do homologous sequences get together for recombination?. Nat Rev Genet 9, 27–37 (2008). https://doi.org/10.1038/nrg2224
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