Brain cell somatic gene recombination and its phylogenetic foundations.
J Biol Chem
; 295(36): 12786-12795, 2020 09 04.
Article
en En
| MEDLINE
| ID: mdl-32699111
ABSTRACT
A new form of somatic gene recombination (SGR) has been identified in the human brain that affects the Alzheimer's disease gene, amyloid precursor protein (APP). SGR occurs when a gene sequence is cut and recombined within a single cell's genomic DNA, generally independent of DNA replication and the cell cycle. The newly identified brain SGR produces genomic complementary DNAs (gencDNAs) lacking introns, which integrate into locations distinct from germline loci. This brief review will present an overview of likely related recombination mechanisms and genomic cDNA-like sequences that implicate evolutionary origins for brain SGR. Similarities and differences exist between brain SGR and VDJ recombination in the immune system, the first identified SGR form that now has a well-defined enzymatic machinery. Both require gene transcription, but brain SGR uses an RNA intermediate and reverse transcriptase (RT) activity, which are characteristics shared with endogenous retrotransposons. The identified gencDNAs have similarities to other cDNA-like sequences existing throughout phylogeny, including intron-less genes and inactive germline processed pseudogenes, with likely overlapping biosynthetic processes. gencDNAs arise somatically in an individual to produce multiple copies; can be functional; appear most frequently within postmitotic cells; have diverse sequences; change with age; and can change with disease state. Normally occurring brain SGR may represent a mechanism for gene optimization and long-term cellular memory, whereas its dysregulation could underlie multiple brain disorders and, potentially, other diseases like cancer. The involvement of RT activity implicates already Food and Drug Administration-approved RT inhibitors as possible near-term interventions for managing SGR-associated diseases and suggest next-generation therapeutics targeting SGR elements.
Palabras clave
Alzheimer disease; DNA recombination; VDJ recombination; copy-number variation (CNV); genomic mosaicism; genomics; intron loss; neurodegenerative disease; neuron; neurons; postmitotic; processed pseudogenes; reverse transcription; single-nucleotide variation (SNV); somatic cell genetics; somatic gene recombination; yeast genetics; yeast genomes
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Recombinación Genética
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Encéfalo
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ADN Polimerasa Dirigida por ARN
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Precursor de Proteína beta-Amiloide
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Elementos de Nucleótido Esparcido Largo
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Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos