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Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis

Key Points

  • Homologous recombination maintains genomic stability in mammalian mitotic cells through precise templated repair of DNA double-strand breaks and other lesions. The outcome of homologous recombination is typically precise when the sister chromatid is the donor template.

  • Homologous recombination is a coordinated process involving the RAD51 strand exchange protein and numerous other proteins that promote RAD51 function. RAD51 forms a filament on single-stranded DNA that is generated by end resection.

  • Precise repair is promoted by both regulated expression and activation of factors involved in homologous repair during the S and G2 phases of the cell cycle.

  • Alternative templates for repair that encompass some degree of heterology have the potential to be mutagenic, with the occurrence of loss of heterozygosity or rearrangements. Most rearrangements occur by alternative DNA double-strand break repair pathways that do not involve homology.

  • Mammalian cells that are defective for homologous recombination components have spontaneous and damage-induced genomic instability, mild ionizing radiation sensitivity and severe sensitivity to DNA cross-linking agents.

  • In humans, biallelic defects in the homologous recombination factors breast and ovarian cancer type 2 susceptibility protein (BRCA2), partner and localizer of BRCA2 (PALB2) and BRCA1-interacting protein 1 (BRIP1) result in Fanconi anaemia, and mono-allelic defects in BRCA2, BRCA1, PALB2 and BRIP1 result in a predisposition to breast cancer. Other human tumours are associated with the loss of BRCA2, BRCA1 and PALB2.

Abstract

Mitotic homologous recombination promotes genome stability through the precise repair of DNA double-strand breaks and other lesions that are encountered during normal cellular metabolism and from exogenous insults. As a result, homologous recombination repair is essential during proliferative stages in development and during somatic cell renewal in adults to protect against cell death and mutagenic outcomes from DNA damage. Mutations in mammalian genes encoding homologous recombination proteins, including BRCA1, BRCA2 and PALB2, are associated with developmental abnormalities and tumorigenesis. Recent advances have provided a clearer understanding of the connections between these proteins and of the key steps of homologous recombination and DNA strand exchange.

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Figure 1: Pathways of DNA DSB repair.
Figure 2: Mechanism of HR revealed by RecA–ssDNA and RecA–dsDNA structures.
Figure 3: Homologous templates and repair outcomes of HR.
Figure 4: HR protein interactions and domains.

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Acknowledgements

The authors thank past and present members of the laboratory, especially E. Kass, and colleagues in the field for discussions. Work in the authors' laboratory is supported the Hecksher Foundation for Children (M.E.M.) and National Institutes for Health grants P01CA94060 (M.E.M and M.J.) and R01GM54668 (M.J.).

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Glossary

B-form DNA

The most common helical DNA structure, also called canonical DNA, comprising two aligned strands of DNA in opposite polarity forming a right-handed helix.

Non-crossover

Homologous recombination in which DNA sequences are copied from the donor strand to the recipient strand without an exchange of genetic information with the recipient strand flanking DNA.

Holliday junction

A structural intermediate formed between four DNA strands during homologous recombination.

Crossover

Resolution of homologous recombination resulting in an exchange of DNA sequences between the donor and recipient.

Loss of heterozygosity

Reduction of genetic information from both maternal and paternal alleles to genetic information from a single parent.

Centrosome

A cytoplasmic organelle that organizes microtubules. Preceding mitosis, the centrosome doubles and then is involved in the generation of the mitotic spindle for subsequent chromosome segregation during mitosis.

Fanconi anaemia

A genetic disorder arising from biallelic mutations in one of 13 different genes, characterized by chromosome instability that typically presents early in life, with developmental disorders, anaemia, bone marrow failure and solid and haematologic malignancy. There is a high degree of clinical variation that depends on both the gene defect and mutation type.

Somatic mosaicism

The existence of more than one genetically distinct population of somatic cells in an organism. This can arise by DNA mutation, chromosome non-disjunction, recombination or the spontaneous reversion of inherited mutations.

E3 ubiquitin ligase

A ubiquitin ligase that, in combination with an E2 ubiquitin-conjugating enzyme, adds ubiquitin (a 76-amino acid protein) to a Lys on a target protein.

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Moynahan, M., Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11, 196–207 (2010). https://doi.org/10.1038/nrm2851

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