01
Coordinated inheritance of extrachromosomal DNAs in cancer cells
Hung KL, et al.
Nature, 2024
Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification. It raises the hypothesis that the co-occurrence of multiple ecDNA sequences in a cell may have combinatorial and synergistic effects on transcriptional programs. In this paper, the authors first analyzed ecDNA structures predicted from whole-genome sequencing data. They found that most tumors contained two or more ecDNA species in the same tumor. Next, they evaluated copy-number correlations in cells across different phases of the cell cycle using the single-cell multi-omics data. Using DNA-FISH combined with immunofluorescence staining, they quantified the copy numbers of ecDNA inherited among daughter cell pairs. And they suggested that collectives of ecDNA species may co-segregate during mitosis. They also visualized ecDNA hubs during mitosis using live-cell imaging, and observed in many cases that hubs of ecDNA molecules remained as a unit throughout mitosis. Importantly, they identified an ecDNA species in the SNU16 gastric cancer cell line that contains no oncogene-coding sequences but containing accessible chromatin. The presence of amplified enhancer elements in the pool of ecDNA molecules supports enhancer-promoter interactions in trans and further upregulate oncogene expression. An enhancer-only ecDNA may be especially sensitive to the co-occurrence of oncogene-coding ecDNAs in the same ecDNA hubs. What’s more, they performed drug treatment on SNU16m1 cancer cell line targeting its specific ecDNA. The results showed that pharmacological targeting of an oncogene carried by one ecDNA species can coordinately regulate co-existing ecDNA species.
DOI: 10.1038/s41586-024-07861-8
02
He HQ, et al.
Nat Aging. 2024
As aging, the functionality of hematopoietic stem cells (HSCs) becomes compromised, evident in the reduced reconstitution capacity and a differentiation bias toward the myeloid lineage. In this paper, the authors aimed to investigate the complete molecular mechanism leading to deterioration of HSCs in response to DNA damage. Firstly, they observed that microcephalin (MCPH1) whose roles encompass diverse cellular functions, including involvement in DNA damage response, exhibits predominant expression in hematopoietic stem and progenitor cells (HSPCs). They generated Vav1-Cre; Mcph1fl/fl mice, resulting in the specific deletion of Mcph1 in hematopoietic cells. They conducted an ex vivo assessment of the proliferation capacity of freshly isolated Mcph1−/− HSCs. And the results showed that the proliferation capacity of Mcph1−/− HSCs was severely compromised. Additionally, Mcph1−/− HSCs exhibited a differentiation bias toward the myeloid lineage. And GSEA uncovered that Mcph1−/− HSCs exhibited enrichment in myeloid proliferation genes. Also, they detected the specific cell death pathway activated upon Mcph1 deletion, and found that necroptosis was activated. They observed that Mcph1−/− HSCs exhibited necroptosis features, including cell swelling. Furthermore, they observed potential interactions between MCPH1, RIPK3 and MLKL by affinity purification of MCPH1 protein complexes. Co-IP assay revealed a robust interaction between MCPH1 and RIPK3. They also proved that the BRCT domain in the C-terminal region of MCPH1 is important in the functional interaction. They then observed that MCPH1 translocated to nucleus in response to DNA damage. They assessed the involvement of the MCPH1nuclear localization signal (NLS) in nuclear translocation, and found that NLS-1 and NLS-2 play a crucial role in mediating MCPH1 nuclear translocation. MCPH1ΔNLS1/2 has a stronger inhibitory effect on necroptosis. They further indicated a decline in the apoptosis pathway in aged HSCs, while necroptosis signaling, represented by p-RIPK3 and p-MLKL, increased. In conclusion, MCPH1 nuclear translocation induced by aging impairs HSCs by releasing RIPK3 and activating necroptosis.
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