V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity

Arya, Rahul; Bassing, Craig H.

doi:10.1016/j.tig.2017.04.006

Cited by 26 publications

(18 citation statements)

References 79 publications

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“…Changes in the genome, particularly rearrangements or significant sequence loss, can be deleterious leading to disease or inviability. However, there are exceptions to this genome constancy, including gene rearrangements that occur in B-cells and T-cells that expand the repertoire of immunoglobulins and receptors, respectively [1]. Another major exception is programmed DNA elimination.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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Germline and somatic genomes are typically the same in a multicellular organism. However, in some organisms including the parasitic nematode Ascaris, programmed DNA elimination leads to a reduced somatic genome compared to germline cells. Previous work on the parasitic nematode Ascaris demonstrated that programmed DNA elimination encompasses high fidelity chromosomal breaks at specific genome locations and loss of specific genome sequences including a major tandem repeat of 120 bp and ~1,000 germline-expressed genes. However, the precise chromosomal locations of the 120 bp repeats, the breaks regions, and the eliminated genes remained unknown. Here, we used PacBio longread sequencing and chromosome conformation capture (Hi-C) to obtain fully assembled chromosomes of Ascaris germline and somatic genomes, enabling a complete chromosomal view of DNA elimination.Surprisingly, we found that all 24 germline chromosomes undergo comprehensive chromosome end remodeling with DNA breaks in their subtelomeric regions and loss of distal sequences including the telomeres at both chromosome ends. All new Ascaris somatic chromosome ends are recapped by de novo telomere healing. We provide an ultrastructural analysis of DNA elimination and show that Ascaris eliminated DNA is incorporated into many double membrane-bound structures, similar to micronuclei, during telophase of a DNA elimination mitosis. These micronuclei undergo dynamic changes including loss of active histone marks and localize to the cytoplasm following daughter nuclei formation and cytokinesis where they form autophagosomes. Comparative analysis of nematode chromosomes suggests that germline chromosome fusions occurred forming Ascaris sex chromosomes that become independent chromosomes following DNA elimination breaks in somatic cells. These studies provide the first chromosomal view and define novel features and functions of metazoan programmed DNA elimination.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Wang

Veronezi

Zagoskin

et al. 2020

Preprint

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“…In human tissues, relative copy numbers of LINE-1 retrotransposon are higher in the brain than in non-neural tissue, although the role of LINE-1 retrotransposition in neural development remains controversial 24,25 . In addition to LINE-1, recent studies have characterized several endonucleases responsible for the generation of sequence-directed DNA breaks in adult neurons 26 and other cell types 27 . In the immune system, the endonuclease RAG-1,2-complex is responsible for generating directed DSBs at sequence-specific targets and regulates DNA repair, primarily via the NHEJ pathway 28,29 .…”

Section: Introductionmentioning

confidence: 99%

RAG-2 deficiency results in fewer phosphorylated histone H2AX foci, but increased retinal ganglion cell death and altered axonal growth

Álvarez-Lindo

Baleriola

Rı́os

et al. 2019

Sci Rep

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DNA double-strand breaks (DSBs), selectively visualized as γ-H2AX+ foci, occur during the development of the central nervous system, including the retina, although their origin and biological significance are poorly understood. Mutant mice with DSB repair mechanism defects exhibit increased numbers of γ-H2AX+ foci, increased cell death during neural development, and alterations in axonogenesis in the embryonic retina. The aim of this study was to identify putative sources of DSBs. One of the identified DSBs sources is LINE-1 retrotransposition. While we did not detect changes in LINE-1 DNA content during the early period of cell death associated with retinal neurogenesis, retinal development was altered in mice lacking RAG-2, a component of the RAG-1,2-complex responsible for initiating somatic recombination in lymphocytes. Although γ-H2AX+ foci were less abundant in the rag2−/− mouse retina, retinal ganglion cell death was increased and axonal growth and navigation were impaired in the RAG-2 deficient mice, a phenotype shared with mutant mice with defective DNA repair mechanisms. These findings demonstrate that RAG-2 is necessary for proper retinal development, and suggest that both DSB generation and repair are genuine processes intrinsic to neural development.

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“…Such events could occur in a genome due to replication defects or exogenous factors such as ionizing radiation or chemotherapeutic agents (11). Multiple DSBs also occur naturally during processes like V(D)J recombination (12). The occurrence of multiple DSBs can also be induced in the micronuclei of cancer cells (13).…”

mentioning

confidence: 99%

Centromere scission drives chromosome shuffling and reproductive isolation

Yadav

Sun

Coelho

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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A fundamental characteristic of eukaryotic organisms is the generation of genetic variation via sexual reproduction. Conversely, significant large-scale genome structure variations could hamper sexual reproduction, causing reproductive isolation and promoting speciation. The underlying processes behind large-scale genome rearrangements are not well understood and include chromosome translocations involving centromeres. Recent genomic studies in theCryptococcusspecies complex revealed that chromosome translocations generated via centromere recombination have reshaped the genomes of different species. In this study, multiple DNA double-strand breaks (DSBs) were generated via the CRISPR/Cas9 system at centromere-specific retrotransposons in the human fungal pathogenCryptococcus neoformans. The resulting DSBs were repaired in a complex manner, leading to the formation of multiple interchromosomal rearrangements and new telomeres, similar to chromothripsis-like events. The newly generated strains harboring chromosome translocations exhibited normal vegetative growth but failed to undergo successful sexual reproduction with the parental wild-type strain. One of these strains failed to produce any spores, while another produced ∼3% viable progeny. The germinated progeny exhibited aneuploidy for multiple chromosomes and showed improved fertility with both parents. All chromosome translocation events were accompanied without any detectable change in gene sequences and thus suggest that chromosomal translocations alone may play an underappreciated role in the onset of reproductive isolation and speciation.

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V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity

Cited by 26 publications

References 79 publications

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

Comprehensive Chromosome End Remodeling During Programmed DNA Elimination

RAG-2 deficiency results in fewer phosphorylated histone H2AX foci, but increased retinal ganglion cell death and altered axonal growth

Centromere scission drives chromosome shuffling and reproductive isolation

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