Using chemical genetic screens, scientists identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppressed genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC).
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The authors report the implementation of CRISPR/Cas-9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma cell lines.
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The authors proposed that in addition to ataxia‐telangiectasia and Rad3 related (ATR), a MYBL2‐MRN‐ATM replication stress response pathway functioned in ESCs to control DNA replication initiation and prevent genome instability.
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Researchers demonstrated that loss of DEAD-box Helicase 41 (ddx41) led to anemia caused by diminished proliferation and defective differentiation of erythroid progenitors.
Scientists developed a medium-throughput drug screening system and identified a small molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting SARS-CoV-2 cytopathic effect in human epithelial cells.
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Garcia, G., Sharma, A., Ramaiah, A., Sen, C., Purkayastha, A., Kohn, D. B., Parcells, M. S., Beck, S., Kim, H., Bakowski, M. A., Kirkpatrick, M. G., Riva, L., Wolff, K. C., Han, B., Yuen, C., Ulmert, D., Purbey, P. K., Scumpia, P., Beutler, N., … Arumugaswami, V. (2021). Antiviral Drug Screen Identifies DNA-Damage Response Inhibitor as Potent Blocker of SARS-CoV-2 Replication. Cell Reports, 0(0). https://doi.org/10.1016/j.celrep.2021.108940 Cite
Researchers showed that the replication stress response was efficient in primary CSCs from colorectal cancer, and described unique roles for PARP1 and MRE11/RAD51.
[Cell Death & Differentiation]
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Manic, G., Musella, M., Corradi, F., Sistigu, A., Vitale, S., Soliman Abdel Rehim, S., Mattiello, L., Malacaria, E., Galassi, C., Signore, M., Pallocca, M., Scalera, S., Goeman, F., De Nicola, F., Guarracino, A., Pennisi, R., Antonangeli, F., Sperati, F., Baiocchi, M., … Vitale, I. (2021). Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51. Cell Death & Differentiation, 1–23. https://doi.org/10.1038/s41418-020-00733-4 Cite
In in vitro studies, collagen type VI secretion from human renal glomerular endothelial cells was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium.
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5-AzadC induced HEXIM1 expression in prostate cancer cell lines and triple negative breast cancers. 5-AzadC-induced DNA damage enhanced P-TEFb occupancy via a mechanism that involved activation of ATR and ATM and induction of NF-ĸB recruitment to the HEXIM1 promoter.
Researchers showed that BGB324, a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient non-small cell lung cancer cell lines.
[Molecular Cancer Research]
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Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four POLD1 variants, scientists established heterozygous POLD1-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to inhibition of ATR or its effector kinase CHK1.
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Scientists interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel pancreatic cancer patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids.
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Dreyer, S. B., Upstill-Goddard, R., Paulus-Hock, V., Paris, C., Lampraki, E.-M., Dray, E., Serrels, B., Caligiuri, G., Rebus, S., Plenker, D., Galluzzo, Z., Brunton, H., Cunningham, R., Tesson, M., Nourse, C., Bailey, U.-M., Jones, M., Moran-Jones, K., Wright, D. W., … Chang, D. K. (2020). Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer. Gastroenterology. https://doi.org/10.1053/j.gastro.2020.09.043 Cite