Finding a match: how do homologous sequences get together for recombination?

Barzel, Adi; Kupiec, Martin

doi:10.1038/nrg2224

Cited by 173 publications

(169 citation statements)

References 102 publications

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“…However, before recombination, there needs to be a search in which homologous genes can find each other. The slow process of random diffusion is incompatible with the rate of recombination, 1,2 suggesting that another mechanism is at play. What this might be is an important remaining question in molecular biology.…”

Section: Introductionmentioning

confidence: 99%

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Which way up? Recognition of homologous DNA segments in parallel and antiparallel alignments

Lee

Wynveen

Albrecht

et al. 2015

The Journal of Chemical Physics

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Homologous gene shuffling between DNA molecules promotes genetic diversity and is an important pathway for DNA repair. For this to occur, homologous genes need to find and recognize each other. However, despite its central role in homologous recombination, the mechanism of homology recognition has remained an unsolved puzzle of molecular biology. While specific proteins are known to play a role at later stages of recombination, an initial coarse grained recognition step has, however, been proposed. This relies on the sequence dependence of the DNA structural parameters, such as twist and rise, mediated by intermolecular interactions, in particular, electrostatic ones. In this proposed mechanism, sequences that have the same base pair text, or are homologous, have lower interaction energy than those sequences with uncorrelated base pair texts. The difference between the two energies is termed the "recognition energy." Here, we probe how the recognition energy changes when one DNA fragment slides past another, and consider, for the first time, homologous sequences in antiparallel alignment. This dependence on sliding is termed the "recognition well." We find there is a recognition well for anti-parallel, homologous DNA tracts, but only a very shallow one, so that their interaction will differ little from the interaction between two nonhomologous tracts. This fact may be utilized in single molecule experiments specially targeted to test the theory. As well as this, we test previous theoretical approximations in calculating the recognition well for parallel molecules against MC simulations and consider more rigorously the optimization of the orientations of the fragments about their long axes upon calculating these recognition energies. The more rigorous treatment affects the recognition energy a little, when the molecules are considered rigid. When torsional flexibility of the DNA molecules is introduced, we find excellent agreement between the analytical approximation and simulations. C 2015 AIP Publishing LLC. [http://dx

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Section: Introductionmentioning

confidence: 99%

“…Indeed, there is evidence to suggest that before strand breakage occurs, identical intact double-stranded DNA segments may pair. 1,[9][10][11][12] It is also conceivable that homology recognition between intact DNA tracts may occur in other biological processes. One instance might be the silencing of multiple copies of the same gene.…”

Section: Introductionmentioning

confidence: 99%

Which way up? Recognition of homologous DNA segments in parallel and antiparallel alignments

Lee

Wynveen

Albrecht

et al. 2015

The Journal of Chemical Physics

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“…A recent study in mice reported that a DSB-independent mechanism promotes homolog pairing during premeiotic S phase prior to DSB formation (Boateng et al 2013). The molecular mechanism of DSB-independent homolog recognition remains a mystery, although the aggregation of heterochromatin, noncoding RNA, the SPO11 protein, or sequence-specific DNA-binding proteins such as transcription factors are suggested to contribute to this process (Page and Hawley 2004;Barzel and Kupiec 2008;Dombecki et al 2011;Ding et al 2012;Boateng et al 2013).…”

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confidence: 99%

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

Ishiguro¹,

et al. 2014

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During meiosis, homologous chromosome (homolog) pairing is promoted by several layers of regulation that include dynamic chromosome movement and meiotic recombination. However, the way in which homologs recognize each other remains a fundamental issue in chromosome biology. Here, we show that homolog recognition or association initiates upon entry into meiotic prophase before axis assembly and double-strand break (DSB) formation. This homolog association develops into tight pairing only during or after axis formation. Intriguingly, the ability to recognize homologs is retained in Sun1 knockout spermatocytes, in which telomere-directed chromosome movement is abolished, and this is the case even in Spo11 knockout spermatocytes, in which DSB-dependent DNA homology search is absent. Disruption of meiosis-specific cohesin RAD21L precludes the initial association of homologs as well as the subsequent pairing in spermatocytes. These findings suggest the intriguing possibility that homolog recognition is achieved primarily by searching for homology in the chromosome architecture as defined by meiosis-specific cohesin rather than in the DNA sequence itself.

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“…This finding might suggest that, upon DNA breakage, homology search between sister chromatids is faster than homologs in mitosis, likely because sisters are connected by cohesion. In fact, while compelling data indicate that meiosis specific proteinaceous structures, called the synaptonemal complex, connects the homologs facilitating DNA exchange, there are contradictory observations that homologs pair in mitotic cell cycle [9]. Bzymek et al also found that the levels of mitotic inter-homologue junctions are remarkably lower compared to those of meiotic junctions, although the rates of DSB formation were comparable in the two contexts.…”

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confidence: 94%