53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress

Lukas, Claudia, Savic, Velibor, Bekker-Jensen, Simon, Doil, Carsten, Neumann, Beate, Pedersen, Ronni Sølvhøj, Grøfte, Merete, Chan, Kok Lung, Hickson, Ian David, Bartek, Jiri and Lukas, Jiri (2011) 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nature Cell Biology, 13 (3). pp. 243-253. ISSN 1465-7392

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Abstract

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

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical Medicine
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Depositing User: Velibor Savic
Date Deposited: 11 Feb 2013 14:07
Last Modified: 14 May 2015 09:43
URI: http://sro.sussex.ac.uk/id/eprint/43584
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