Abstract
Still unresolved is the question of how a lifetime accumulation of somatic gene copy number alterations impact organ functionality and aging and age-related pathologies. Such an issue appears particularly relevant in the broadly post-mitotic central nervous system (CNS), where non-replicative neurons are restricted in DNA-repair choices and are prone to accumulate DNA damage, as they remain unreplaced over a lifetime. Both DNA injuries and consecutive DNA-repair strategies are processes that can evoke extrachromosomal circular DNA species, apparently from either part of the genome. Due to their capacity to amplify gene copies and related transcripts, the individual cellular load of extrachromosomal circular DNAs will contribute to a dynamic pool of additional coding and regulatory chromatin elements. Analogous to tumor tissues, where the mosaicism of circular DNAs plays a well-characterized role in oncogene plasticity and drug resistance, we suggest involvement of the “circulome” also in the CNS. Accordingly, we summarize current knowledge on the molecular biogenesis, homeostasis and gene regulatory impacts of circular extrachromosomal DNA and propose, in light of recent discoveries, a critical role in CNS aging and neurodegeneration. Future studies will elucidate the influence of individual extrachromosomal DNA species according to their sequence complexity and regional distribution or cell-type-specific abundance.
Highlights
Extrachromosomal circular DNA, which is highly conserved across yeast, plants and mammals [1], was first described by Alix Bassel and Yasuo Hoota in 1964 [2]
Cellular senescence is described to progress through different stages, with the later phase being characterized by the transcriptional de-repression of transposable elements (TEs), accompanied by a sterile inflammation elicited through an interferon-dependent immune response against cytoplasmic TE DNA [88,89,117]
It has been proposed that mechanisms involved in the generation of eccDNA could serve as biomarkers and therapeutic targets in the frame of oncogene-associated pathologies [112]
Summary
Extrachromosomal circular DNA (eccDNA/ecDNA), which is highly conserved across yeast, plants and mammals [1], was first described by Alix Bassel and Yasuo Hoota in 1964 [2]. Apart from non-dividing neurons, the brain harbors glial populations with reactive mitotic potential, which can contribute to HR-related eccDNA formation and account for events of eccDNA generation by break-independent replication errors It is well-established that, under certain stress conditions, post-mitotic neurons can reactivate an abortive cell cycle at least up to an S phase that is entailed by partial or complete DNA replication [45,46,47,48]. Whether the prevalence of repetitive elements such as telomeric and interspersed sequences arises either from HR or, in light of the low proliferative activity of differentiated non-damaged muscle, from a continuous excision of repetitive sequences from the genome, requires further investigation [19] Considering such evidence, deletions of any chromosomal origin, including spontaneous deletions or those arising from DNA-repair mechanisms, might give rise to eccDNA both in replicative and post-mitotic tissues and organs
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