Abstract
The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.
Highlights
The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle
While other reviews have broadly discussed genomic stability in the nervous system [10,12,22], here, we will focus on studies that have contributed to our current understanding about how replication stress is generated across the diverse cell types in the central nervous system (CNS), what players mediate replication stress response (RSR), and what the consequences are for CNS development and homeostasis when the RSR is defective
Since ATM was only required for DNA damage-induced apoptosis in differentiating progenitor cells, it was proposed that these kinases may have unique and nonoverlapping functions in the developing
Summary
The maintenance of genomic stability is crucial for human health. In proliferating cells, precise. Genetic studies of inherited syndromes have established a clear connection between mutations in DNA damage response (DDR) genes and several human diseases [11]. Highlighting the importance of genomic integrity, several other inherited syndromes that affect the CNS development and function are caused by mutations in genes involved in the generation or in the responses to replication stress [3]. While other reviews have broadly discussed genomic stability in the nervous system [10,12,22], here, we will focus on studies that have contributed to our current understanding about how replication stress is generated across the diverse cell types in the CNS, what players mediate RSR, and what the consequences are for CNS development and homeostasis when the RSR is defective
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