1. 53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage.
- Author
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Spies J, Lukas C, Somyajit K, Rask MB, Lukas J, and Neelsen KJ
- Subjects
- Cell Line, Chromosome Segregation, DNA Repair, DNA Replication, Humans, Rad52 DNA Repair and Recombination Protein metabolism, Recombination, Genetic, S Phase genetics, Telomere-Binding Proteins physiology, Cell Nucleus Structures physiology, DNA Damage, DNA Replication Timing, Tumor Suppressor p53-Binding Protein 1 physiology
- Abstract
Failure to complete DNA replication is a stochastic by-product of genome doubling in almost every cell cycle. During mitosis, under-replicated DNA (UR-DNA) is converted into DNA lesions, which are inherited by daughter cells and sequestered in 53BP1 nuclear bodies (53BP1-NBs). The fate of such cells remains unknown. Here, we show that the formation of 53BP1-NBs interrupts the chain of iterative damage intrinsically embedded in UR-DNA. Unlike clastogen-induced 53BP1 foci that are repaired throughout interphase, 53BP1-NBs restrain replication of the embedded genomic loci until late S phase, thus enabling the dedicated RAD52-mediated repair of UR-DNA lesions. The absence or malfunction of 53BP1-NBs causes premature replication of the affected loci, accompanied by genotoxic RAD51-mediated recombination. Thus, through adjusting replication timing and repair pathway choice at under-replicated loci, 53BP1-NBs enable the completion of genome duplication of inherited UR-DNA and prevent the conversion of stochastic under-replications into genome instability.
- Published
- 2019
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