Boon and Bane of DNA Double-Strand Breaks
2. Unrepaired DSBs Can Be Lethal for Dividing Cells
3. DSBs Can Be Repaired by Diverse Mechanisms
4. DSB Repair Generates Diverse Phenomena
5. Deleterious and Beneficial Consequences of DSB Repair
- DSBs which are programmed during meiotic prophase I are repaired in their majority without genetic consequences; a minority, via cross-over with the homologous allele, result in a new combination of maternal and paternal alleles. Cross-overs keep maternal and paternal homologous chromosomes together until reductional anaphase I, and thus enable correct segregation of parental chromosomes into gametes. The new combination of parental alleles, if beneficial for survival (and propagation) of its carriers, will be positively selected in the next generations.
- Chromosome translocations in the heterozygous state potentially reduce the fertility of carriers (due to the risk of lethality after unbalanced segregation) (Figure 4). Heterozygous inversions, if the corresponding regions engage in crossing over, will yield duplications and deletions, which are mostly lethal. Chromosome rearrangements will be eliminated if carriers bear negative features. If, however, their effect is superior to the ancestral genotype/karyotype, after passing the bottle neck towards homozygosity, the progeny will be positively selected. Such positive effects may be differential gene expression or advantageous linkage of distinct alleles, for instance. In the homozygous condition, positively selected chromosome rearrangements, and even selectively neutral ones, may contribute as initial events towards speciation (for review: ), because usually they act as fertility barriers.
- While the correct DSB repair during meiotic prophase I results in cross-overs and leads to new combinations of pre-existing alleles, mis-repair of DSBs at any developmental stage can lead to deletion (via end-digestion), or to sequence insertion (e.g., via conversion of more than the missing sequence, via transposon invasion or via alien chromatin introgression in interspecific hybrids used in crop breeding; see Figure 1) into the break. Deletions and/or insertions create a genetic novelty which is either positive, negative or selectively neutral. Positive or neutral mutations increase genetic diversity; the latter as a playground for future mutation and selection processes.
- If there is a (genetically fixed) bias of DSB repair towards either deletions or insertions, shrinking or expansion of the genome would be the corresponding long-term consequence in a population, as long as the bias is maintained (Figure 5; for review: ). This might explain the C-value paradox , which means that the genome size is not correlated with the genetic complexity of organisms.
- In particular, genome expansion via active retroelement amplification and dispersion is eventually the result of DSB repair  biased towards insertion mediated by a retroelement-encoded integrase.
- Erroneous repair of DSBs can generate such primary chromosome rearrangements which can in turn be linked directly and/or via meiotic segregation errors with dysploid chromosome number alteration in both directions (Figure 6) (for review: ). Reciprocal translocation with breakpoints close to the centric ends of two acro- or telocentric chromosomes, which yield a large metacentric product and a small centric (or acentric) one, can reduce the chromosome number, if subsequent meiotic loss of the small product is tolerated  (Figure 6A). Similarly, insertion of a chromosome with breakpoints at both termini into a break within the centromere of a recipient chromosome reduces the chromosome number, if two telomeres and one centromere get lost or the recipient centromere becomes inactive (Figure 6B; ). If a metacentric gets broken in the centromere region in a way in which both fragments maintain centromere function and get stabilized by telomeric sequences, the chromosome number increases (Figure 6C, arrow to the left). This process can be reversible by translocation between these novel centric ends (Figure 6B, arrow to the right).
- In addition to primary rearrangements (deletion, inversion, translocation), secondary rearrangements (Figure 7) also depend on DSBs. Secondary rearrangements may occur in individuals which are heterozygous for two rearrangements with one chromosome involved in both rearrangements. If meiotic cross-over takes place between partially homozygous regions of rearranged chromosomes (flanked by different regions on either side of the cross-over), a newly rearranged chromosome segregates to one daughter nucleus and the re-established wild-type chromosome to the other. This pathway was also experimentally proven for plants, and might occur in other eukaryotes as well (for review: ).
- Programmed DSBs take place during V(D)J-recombination of immunoglobulin genes in the adaptive immune system of vertebrates (for review: [18,19]). Immunoglobulins are the antibodies which recognize and neutralize antigenic proteins of invading pathogens, thus mediating disease resistance. In case of pathologic overreaction of the immune system, antibodies can cause allergies, when directed against harmless environmental antigens, or autoimmune diseases when directed against the body’s own proteins.
- DSBs, mediated by ‘domesticated’ transposases, play an essential role in chromatin elimination. Chromatin elimination (or diminution) occurs, e.g., in protozoans, where the chromosomes of generative micronucleus are fragmented into many, much smaller (sometimes gene-sized) chromosomes of the vegetative macronucleus, removing the interspersed repetitive sequences (for review: ), or in somatic stem cells of roundworms (e.g., ). Exceptionally, B chromosomes can be eliminated from plant organs .
- Programmed cell death (apoptosis) is another phenomenon accompanied by endonuclease-mediated DSBs, degrading nuclear DNA into small pieces (for review: ). Apoptosis represents a developmentally or extrinsically triggered suicidal cell destruction.
- Cancerogenesis of several tissues is also considered to start with multiple chromosome breaks as a consequence of a sudden genotoxic stress in a single cell. Such an event of catastrophic accumulation of DSBs (chromosome pulverization) and subsequent mis-repair leads simultaneously to dozens to hundreds of chromosomes rearrangements (Figure 8). The phenomenon is called chromothripsis . The derivatives of the affected cell will mostly die (bottle neck) until viable versions (the malign cells) with the ability of rapid propagation prevail. This process is called evolution by several researchers (for review: ). True cancerogenesis is not known for plants. Nevertheless, multiple breakages and rearrangements occur during plant evolution (e.g., ). However, we cannot be sure whether evolutionarily fixed events appeared in a single cell, or subsequently over generations.
6. Targeted DSBs Can Modify Genetic Information for Research, Breeding and Gene Therapy
7. Concluding Remarks
Conflicts of Interest
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Schubert, I. Boon and Bane of DNA Double-Strand Breaks. Int. J. Mol. Sci. 2021, 22, 5171. https://doi.org/10.3390/ijms22105171
Schubert I. Boon and Bane of DNA Double-Strand Breaks. International Journal of Molecular Sciences. 2021; 22(10):5171. https://doi.org/10.3390/ijms22105171Chicago/Turabian Style
Schubert, Ingo. 2021. "Boon and Bane of DNA Double-Strand Breaks" International Journal of Molecular Sciences 22, no. 10: 5171. https://doi.org/10.3390/ijms22105171