53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress
By C. Lukas, Velibor Savic, Simon Bekker-Jensen, C. Doil, Beate Neumann, R. Pedersen, Merete Grøfte, Kok-Lung Chan, Ian D. Hickson, J. Bartek and 1 more. Nature Cell Biology, 2011
680 citations recorded by the source corpus.
Completion of genome duplication is challenged by structural and topological barriers that impede progression of replication forks. Although this can seriously undermine genome integrity, the fate of DNA with unresolved replication intermediates is not known. Here, we show that mild replication stress increases the frequency of chromosomal lesions that are transmitted to daughter cells. Throughout G1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1) and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclear bodies increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations.
Subfields: Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/3cbcf5d6e04002f896f59021a3244834246883cc
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Citations in the corpus
- ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. (2017, background): “Another class of ATM- and H2AX-dependent, transcriptionally repressed chromatin foci are 53BP1-OPT domains, which form specifically in G1 phase cells around DNA lesions carried over from the previous cell cycle (Harrigan et al., 2011; Lukas et al., 2011).”
- DNA replication stress as a hallmark of cancer. (2015, background): “Specifically, regions of unreplicated DNA may form ultrafine anaphase bridges, which interfere with chromosome segregation during mitosis, resulting in DNA damage in the next cell cycle and genomic instability (124, 125).”
- ATR prohibits replication catastrophe by preventing global exhaustion of RPA. (2013, neutral): “Although clearly triggered by replication stress, CFS breakage does not occur in S phase, but only inmitosis (Harrigan et al., 2011; Lukas et al., 2011).”