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Mechanism of homologous recombination: mediators and helicases take on regulatory functions

Nature Reviews Molecular Cell Biology volume 7, pages 739–750 (2006)Cite this article

Key Points

  • Homologous recombination (HR) has an important role in DNA repair, DNA replication, meiotic chromosome segregation and telomere maintenance. HR is tightly regulated by DNA helicases. A defect in, or deregulation of, HR can lead to cell-cycle arrest, genome destabilization and cancer formation.

  • DNA double-stranded breaks (DSBs) that are caused by exposure to ionizing radiation and other DNA-damaging agents are strong inducers of HR. Programmed HR processes such as meiotic recombination and yeast mating-type switching are initiated through DSB formation.

  • Several HR pathways that are initiated by DSBs have been elucidated. In the DNA double-strand-break repair (DSBR) pathway, a DNA intermediate that contains two Holliday junctions is made. Resolution of this DNA intermediate can produce crossover recombinants that harbour a reciprocal exchange of the arms of the recombining chromosomes.

  • Crossovers are crucial for chromosome segregation at meiosis I, but their formation is suppressed in mitotic cells because of an inherent risk of chromosome rearrangements if the crossovers involve repetitive sequences in the genome.

  • HR is mediated by a class of enzymes known as recombinases. There are two eukaryotic recombinases, RAD51 and DMC1, and both are related to the bacterial recombinase RecA. RAD51 is needed for mitotic and meiotic HR, whereas DMC1 functions only during meiosis.

  • All the recombinases form a helical filament on ssDNA, better known as the presynaptic filament. Assembly of the presynaptic filament requires ATP and is facilitated by recombination mediators, which include the yeast Rad52 protein and the human BRCA2 tumour suppressor.

  • HR is regulated by DNA helicases at several stages. The yeast Mer3 helicase promotes meiotic crossover formation, whereas the yeast Sgs1 and human BLM helicases mediate the dissolution of the double Holliday junction to yield non-crossover recombinants. Moreover, the yeast Srs2 helicase attenuates HR by dismantling the Rad51 presynaptic filament.

  • Many questions concerning the mechanism and regulation of mitotic and meiotic HR remain. For example, how HR functionally synergizes with the Fanconi anaemia protein complex to mediate the removal of interstrand DNA crosslinks remains to be delineated.

Abstract

Homologous recombination (HR) is an important mechanism for the repair of damaged chromosomes, for preventing the demise of damaged replication forks, and for several other aspects of chromosome maintenance. As such, HR is indispensable for genome integrity, but it must be regulated to avoid deleterious events. Mutations in the tumour-suppressor protein BRCA2, which has a mediator function in HR, lead to cancer formation. DNA helicases, such as Bloom's syndrome protein (BLM), regulate HR at several levels, in attenuating unwanted HR events and in determining the outcome of HR. Defects in BLM are also associated with the cancer phenotype. The past several years have witnessed dramatic advances in our understanding of the mechanism and regulation of HR.

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Figure 1: Biological roles of HR.
Figure 2: Repair of DNA double-strand breaks by DSBR and SDSA.
Figure 3: Recombinase filament and displacement-loop formation.
Figure 4: DMC1: rings versus filaments.
Figure 5: Action of recombination mediators.
Figure 6: Regulation of HR by Srs2 and BLM helicases.

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Acknowledgements

We are grateful to M. Sehorn for providing the electron micrographs in Figure 4 and to J. San Filippo and W. Bussen for their help in preparing the figures. We apologize to colleagues whose work could not be cited because of space limitations. The studies in the laboratories of the authors have been supported by research grants from the US National Institutes of Health, the US Department of Defense and the Susan G. Komen Breast Cancer Foundation.

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  1. Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Patrick Sung

  2. Department of Biochemistry and Kaplan Comprehensive Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, 10016, New York, USA

    Hannah Klein

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DNA repair genes

Human DNA repair genes

Glossary

Meiosis I

The successful completion of meiosis requires two cell divisions. Meiosis I refers to the first division in which the pairs of homologous chromosomes are segregated into the two daughter cells.

Fanconi anaemia

(FA). A genetically inherited anaemia that leads to bone marrow failure. Patients with FA are also susceptible to acute myelogenous leukaemia and squamous cell carcinomas in multiple organs. The disease is genetically complex.

Mating-type switching

Haploid S. cerevisiae cells can be of one of two mating types. Only cells of opposite mating types can mate to form a diploid. Cells can switch their mating type through an HR-dependent process.

Crossover

One of the possible outcomes of a physical exchange between duplex DNA molecules. Crossover can occur between sister chromatids or between the non-sister chromatids of a homologous pair of chromosomes. Crossover between non-sister chromatids results in new combinations of parental alleles on the crossover chromosomes.

DNA helicase

An enzyme that uses the energy from ATP hydrolysis to separate the two DNA strands in a double helix.

Post-replication DNA repair

A process that repairs gaps on newly replicated DNA using a DNA polymerase. The gaps usually occur opposite adducts or other lesions on the template strand. Post-replication repair fills in the gaps but does not remove the lesions from the template strand DNA.

Endonuclease

An enzyme that catalyses hydrolytic cleavage of DNA in the middle of a DNA strand or a double helix.

Chromatin immunoprecipitation

A technique for determining whether a protein binds to a particular region of the genome in vivo. It involves treating live cells with formaldehyde to form nonspecific crosslinks between the DNA and any associated proteins. The cells are then lysed, the genomic DNA is sheared into small fragments and the protein of interest is immunoprecipitated. Any protein-associated DNA is then removed and analysed by PCR.

Holliday junction

A cruciform DNA structure that is generated during the synaptic phase of homologous recombination. It is named after Robin Holliday, who proposed its existence in 1964.

Epistasis group

A group of genes that are most frequently defined by double-mutant analyses and function in the same biological pathway.

Orthologue

The structural and functional equivalent of a gene or protein in a different species.

Paralogue

A protein that shares some relatedness in sequence with another protein but not necessarily in function. Paralogues arise through gene duplication.

Loss of heterozygosity

(LOH). Loss of biallelic information at a gene or chromosome region through a number of events, including homologous recombination and deletions. LOH can reveal recessive mutations and is often associated with tumours.

DNA-damage checkpoint

A signal-transduction response that is triggered by DNA damage and that results in the arrest (or delay) of cell-cycle progression.

Translesion DNA polymerase

A specialized low-fidelity DNA polymerase that is capable of synthesizing past lesions in the DNA template.

Topoisomerase

An enzyme that removes torsional stress from double-stranded DNA by changing the DNA supercoiling. It accomplishes this goal by breaking and rejoining one, or both, of the DNA strands, thereby inserting or removing superhelical twists.

Hemicatenane

A DNA structure that forms when one strand of a DNA duplex is wound around a strand from another duplex DNA molecule. Newly replicated sister chromatids are thought to harbour hemicatenanes.

Ubiquitin ligase

An enzyme that facilitates the ligation of ubiquitin to target protein substrates by acting as an intermediary between a ubiquitin-conjugating enzyme and a substrate.

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Sung, P., Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7, 739–750 (2006). https://doi.org/10.1038/nrm2008

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