Regulation of Homologous Recombination in Eukaryotes

Heyer, Wolf Dietrich; Ehmsen, Kirk T.; Liu, Jie

doi:10.1146/annurev-genet-051710-150955

Cited by 906 publications

(898 citation statements)

References 176 publications

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“…Breaks are repaired by DNA end resection followed by invasion of the resulting 3ʹ-single-stranded DNA (ssDNA) tail into the homologous sister chromatid to form a D-loop structure, which then serves as an initiation site for subsequent DNA synthesis [24]. HR often leads to the formation of DNA joint molecules in which the two recombining DNAs are covalently connected by a four-way DNA junction or Holliday junction (HJ) [25–27].…”

Section: The Origin Of Hr-ufbsmentioning

confidence: 99%

A new class of ultrafine anaphase bridges generated by homologous recombination

Chan

West

2018

Cell Cycle

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Ultrafine anaphase bridges (UFBs) are a potential source of genome instability that is a hallmark of cancer. UFBs can arise from DNA catenanes at centromeres/rDNA loci, late replication intermediates induced by replication stress, and DNA linkages at telomeres. Recently, it was reported that DNA intertwinements generated by homologous recombination give rise to a new class of UFBs, which have been termed homologous recombination ultrafine bridges (HR-UFBs). HR-UFBs are decorated with PICH and BLM in anaphase, and are subsequently converted to RPA-coated, single-stranded DNA bridges. Breakage of these sister chromatid entanglements leads to DNA damage that can be repaired by non-homologous end joining in the next cell cycle, but the potential consequences include DNA rearrangements, chromosome translocations and fusions. Visualisation of these HR-UFBs, and knowledge of how they arise, provides a molecular basis to explain how upregulation of homologous recombination or failure to resolve recombination intermediates leads to the development of chromosomal instability observed in certain cancers.

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Section: The Origin Of Hr-ufbsmentioning

confidence: 99%

A new class of ultrafine anaphase bridges generated by homologous recombination

Chan

West

2018

Cell Cycle

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“…For instance, why does initial recognition involve 8-nt (as opposed to 6 or 9), and does the length of microhomology required for initial recognition vary with reaction temperature? How do other recombination proteins, such as members of the Rad52 epistasis group of genes, [3][4][5] modulate dsDNA sampling by Rad51, and what is their impact on strand invasion? Finally, how is dsDNA sampling and capture influenced by the presence of chromatin and other dsDNA-binding proteins?…”

Section: Closing Thoughtsmentioning

confidence: 99%

“…1,2 Strand exchange reactions play essential roles in double-strand DNA break (DSB) repair, the rescue of stalled or collapsed replication forks, chromosomal rearrangements, and horizontal gene transfer. [3][4][5] Strand exchange is also necessary during meiosis, allowing for proper chromosome segregation and the generation of new allelic combinations. 6,7 The Rad51/RecA family of DNA recombinases promote homologous recombination in all kingdoms of life.…”

Section: Introductionmentioning

confidence: 99%

On the influence of protein-DNA register during homologous recombination

Greene

2016

Cell Cycle

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Homologous recombination enables the exchange of genetic information between related DNA molecules and is a driving force in evolution. Using single-molecule optical microscopy we have recently shown that members of the Rad51/RecA family of recombinases stabilize paired homologous strand of DNA in precise 3-nt increments. Here we discuss an interesting conceptual implication of these results, which is that the recombinases may actively sense and reorganize their alignment register relative to the bound DNA sequences to ensure optimal base triplet pairing interactions during the early stages of recombination.

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“…In all kingdoms of life cells achieve error free chromosome repair after DSB by using a reference sequence in a sister chromatid or a homologous chromosome through the process of homologous recombination (HR). The molecular mechanism of HR has been worked out in great detail [1], since HR deficiency is a major source of cancer [2]. However, the mystery of how a broken sequence can find its homologous reference sufficiently fast is unsolved [3].…”

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confidence: 99%

Hypothesis: Homologous Recombination Depends on Parallel Search

Elf

2016

Cell Systems

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Having a double stranded break (DSB) of chromosomal DNA is a serious condition for any cell. In all kingdoms of life cells achieve error free chromosome repair after DSB by using a reference sequence in a sister chromatid or a homologous chromosome through the process of homologous recombination (HR). The molecular mechanism of HR has been worked out in great detail [1], since HR deficiency is a major source of cancer [2]. However, the mystery of how a broken sequence can find its homologous reference sufficiently fast is unsolved [3].The problem is that the homologous reference sequence can be anywhere in the cell [4]. Thus, HR has to depend on probing each conceivable chromosome position although this requires unwinding of the double helix and base pairing with the broken chromosome sequence. Even considering recent in vitro measurements revealing rapid sampling with short oligos [5] it would take more than a year to unwind and compare all sequences in a mammalian genome and weeks for yeast genome. If we add the diffusive and topological constraints of moving and aligning the broken chromosome in a dense nucleus, the time scales involved become astronomical, especially considering that the broken ends must also be held together [6]. Still the cell manages to find the homologous sequence in hours [7]. Something fundamental is clearly missing in our understanding of homologous recombination.If it takes too long to solve a problem sequentially it can often be parallelized. Thus, I suggest that the cell makes many short copies of the sequences flanking the DBS and use these to search for the homologous sequence in parallel. This strategy not only parallelizes the search process but also eliminates the need to move the broken chromosome around in a time consuming manner. Although the necessary molecular components to implement such a strategy have already have been characterized, the transformative impact of this strategy on search speed has not been discussed.For example, in Arabidopsis and in human cells, 21 nt RNAs are made, corresponding to the sequences flanking the DBS [8]. These so called diRNA bind to Ago2, which from separate studies, e.g. ref [9], are seen targeting chromosomal promoters or nascent transcripts when programmed by homologous 21 nt microRNA. Thus, the Ago2 diRNA complexes are ideal candidates for searching the genome for sequences homologous to the broken sequence. Ago2 deletions are further known to be deficient in HR and Ago2 is directly binding to the critical HR protein Rad51 even in the absence of the diRNA [10].An RNA corresponding to the diRNA has not been described in bacteria, but the many short ssDNA resection products that are made by the recBCD or addAB systems while processing the DSB ends [11], could play the same role. This would also explain why ssDNA degradation products have lengths of tens of nucleotides [12]. In fact, short pieces of ssDNA bind RecA in vitro and the complex also search for specific sequences in dsDNA [13], but it is not known whether the resection product...

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Regulation of Homologous Recombination in Eukaryotes

Cited by 906 publications

References 176 publications

A new class of ultrafine anaphase bridges generated by homologous recombination

A new class of ultrafine anaphase bridges generated by homologous recombination

On the influence of protein-DNA register during homologous recombination

Hypothesis: Homologous Recombination Depends on Parallel Search

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