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Chromosomal stability and the DNA double-stranded break connection

Abstract

Genome stability is of primary importance for the survival and proper functioning of all organisms. Double-stranded breaks in DNA are important threats to genome integrity because they can result in chromosomal aberrations that can affect, simultaneously, many genes, and lead to cell malfunctioning and cell death. These detrimental consequences are counteracted by two mechanistically distinct pathways of double-stranded break repair: homologous recombination and non-homologous end-joining. Recently, unexpected links between these double-stranded break-repair systems, and several human genome instability and cancer predisposition syndromes, have emerged. Now, interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.

Key Points

  • DNA double-stranded breaks (DSBs) threaten genome integrity because they cause chromosomal aberrations, leading to loss of cell function and cell death.

  • Two mechanistically distinct, and highly conserved, pathways have evolved to repair DSBs — the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. The importance of these pathways in DSB repair is highlighted by the fact that cells with defective HR or NHEJ show widespread chromosomal instability.

  • Recent evidence shows that if endogenously generated DSBs — for example, DSBs created during V(D)J recombination or DNA replication — are not appropriately repaired, they can give rise to chromosomal abnormalities and genomic instability.

  • The proper activation of cell-cycle checkpoints in response to DSBs is also required to prevent chromosomal instability. Chromosomal instability phenotypes can be enhanced by mutations in cell-cycle checkpoint genes.

  • Cellular assays and mouse models are being used to unravel the interactions between components of the DSB-repair pathways and cell-cycle regulators. Work in mice and humans have revealed new links between these repair pathways and certain human cancer predisposition and genome instability syndromes, such as ataxia telangiectasia, Nijmegen breakage syndrome and ataxia telangiectasia-like disorder.

  • Future research is likely to reveal the regulatory networks that coordinate interactions between the different DNA-repair pathways and the cell-cycle checkpoint systems.

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Figure 1: Causes, cellular responses and consequences of DNA double-stranded breaks.
Figure 2: Ataxia-telangiectasia-mutated protein kinase and the cell-cycle checkpoint response to double-stranded breaks.
Figure 3: Double-stranded break repair through homologous recombination.
Figure 4: Foci induced by DNA damage.

Courtesy of L. R. van Veelen, Department of Cell Biology and Genetics, Erasmus University, Rotterdam, the Netherlands.

Figure 5: Double-stranded break repair by non-homologous end-joining.

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Acknowledgements

The authors thank members of the Department of Cell Biology and Genetics for many useful comments on the manuscript. D.C.v.G. is a fellow of the Royal Netherlands Academy of Arts and Sciences (KNAW). Research in our department is supported by the Dutch Cancer Society, the Netherlands Organization for Scientific Research and the European Commission.

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DATABASE LINKS

xeroderma pigmentosum

ataxia telangiectasia

Nijmegen breakage syndrome

BCR

ABL1

chronic myelocytic leukaemia

Tcr

IgH

ATM

Rag1

Rag2

Trp53

Li-Fraumeni

PI(3)K

DNA-PK

RAD52

RAD50

RAD51

RAD52

RAD54

MRE11

NBS1

RPA

RAD51B

RAD51C

RAD51D

XRCC2

XRCC3

DMC1

BRCA1

BRCA2

KU70

KU80

DNA-PKCS

DNA ligase IV

XRCC4

SCID

ataxia telangiectasia-like disorder

Bloom syndrome

Werner syndrome

BLM

WRN

FURTHER INFORMATION

Tokyo Medical University's animations of chromosomal structural abnormalities

V(D)J recombination animation

Glossary

NUCLEOTIDE EXCISION REPAIR

(NER). A DNA-repair pathway that removes ultraviolet-light-induced DNA damage (such as thymidine dimers) and bulky DNA adducts by excising the oligonucleotide that contains the damaged base(s). The single-stranded gap is filled in by using the intact strand as a template.

MISMATCH REPAIR

(MMR). A DNA-repair pathway that removes mismatched bases and corrects the insertion or deletion of short stretches of (repeated) DNA.

PHILADELPHIA CHROMOSOME

Chromosome 22, from which the tip of the q arm has been exchanged for a small region of the q arm of chromosome 9, fusing together the BCR and ABL1 genes.

SPECTRAL KARYOTYPING

(SKY). A karyotyping method that allows all the chromosomes of an organism to be identified in a single metaphase spread. Each chromosome is labelled with chromosome-specific probes that can be visualized as different colours. This technique is useful for identifying certain chromosomal abnormalities.

IMMUNOGLOBULIN

(Ig). Antigen-receptor molecules produced by B cells that consist of two heavy chains and two light chains.

T-CELL RECEPTOR

(Tcr). Antigen-receptor molecules produced by T cells that consist of either α and β, or γ and δ chains.

METAPHASE SPREAD

A collection of chromosomes arrested at the prophase of mitosis. Because the chromosomes are highly condensed at this stage of cell division, they are visible under a light microscope.

ISOTYPE

Class of immunoglobulin (Ig) protein that is determined by the constant region of the IgH gene that is placed nearest to the joining (J) segments. The isotype can switch during development of the B cell.

PARALOGUE

A locus that is homologous to another in the same genome.

RAD51 NUCLEOPROTEIN FILAMENT

A helical filament of RAD51 protein that covers single-stranded DNA. It contains approximately three bases for every RAD51 monomer and six monomers per helical turn. The nucleoprotein filament can pair with homologous double-stranded DNA.

MACROCHROMOSOME

The chicken genome is divided into macro- and minichromosomes. Only macrochromosomes are large enough to be easily observable under a light microscope.

LATENCY TIME

The time required to develop visible signs of disease, for example, a tumour.

HYPOMORPHIC MUTATION

A mutation that does not completely eliminate the wild-type function of a gene and gives a less severe phenotype than a loss-of-function mutation.

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van Gent, D., Hoeijmakers, J. & Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2, 196–206 (2001). https://doi.org/10.1038/35056049

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