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Your search keyword '"De Bruin, R. A. M."' showing total 6 results
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6 results on '"De Bruin, R. A. M."'

4. DNA replication checkpoint promotes G1-S transcription by inactivating the MBF repressor Nrm1.

Author

de Bruin, R. A. M., Kalashnikova, T. I., Asianian, A., Wohlschlegel, J., Chahwan, C., Yates III, J. R., Russell, P., and Wittenberg, C.

Subjects
DNA replication, NUCLEIC acids, GENES, CHEMICAL reactions, PROTEIN kinases
Abstract

The cell cycle transcriptional program imposes order on events of the cell-cycle and is a target for signals that regulate cell-cycle progression, including checkpoints required to maintain genome integrity. Neither the mechanism nor functional significance of checkpoint regulation of the cell-cycle transcription program are established. We show that Nrm1, an MBF-specific transcriptional repressor acting at the transition from G1 to S phase of the cell cycle, is at the nexus between the cell cycle transcriptional program and the DNA replication checkpoint in fission yeast. Phosphorylation of Nrm1 by the Cds1 (Chk2) checkpoint protein kinase, which is activated in response to DNA replication stress, promotes its dissociation from the MBF transcription factor. This leads to the expression of genes encoding components that function in DNA replication and repair pathways important for cell survival in response to arrested DNA replication. [ABSTRACT FROM AUTHOR]

Published
2008
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5. The DNA replication stress checkpoint transcriptional response and its role in replication stress tolerance

Author

Herlihy, A. E. and de Bruin, R. A. M.

Subjects
616.99
Abstract

DNA replication stress is defined as the slowing down or stalling of DNA replication forks. The DNA replication stress checkpoint prevents replication stress from developing into DNA damage and subsequent genome instability. This checkpoint response maintains E2F-dependent cell cycle transcription through inactivation of E2F6. However, the role and importance of transcription in response to replication stress remains largely unknown. Work presented in this thesis shows that in mammalian cells, unlike yeast, active protein synthesis is required for an efficient checkpoint response. Many checkpoint effector proteins, which are E2F targets, are found to be unstable and so require sustained E2F-dependent transcription to maintain levels during replication stress. Maintaining correct protein levels is necessary for specific functions of the checkpoint response - replication fork stalling, stabilisation and protection, and resolving stalled forks after stress. E2F-dependent transcription is therefore required to prevent DNA damage following replication stress. Importantly, maintaining E2F-dependent transcription during replication stress in checkpoint-compromised cells is sufficient to prevent DNA damage. These results suggest that sustained E2F-dependent transcription is a key mechanism in the replication stress response. Activated oncogenes increase E2F activity, driving uncontrolled proliferation, thought to be at the basis of oncogene-induced replication stress, an early event in tumourigenesis. Data presented shows E2F-dependent transcription is also required to prevent DNA damage during oncogene-induced replication stress; suggesting oncogenic cells rely on E2F-dependent transcription for tolerance to high levels of replication stress. Given the important role of E2F-dependent transcription in the replication stress response, the mechanism of E2F6-dependent repression is also investigated. Overall my work establishes that E2F-dependent transcription is a key mechanism in the response to DNA replication stress and is necessary during oncogene-induced replication stress. The regulation and functions of this transcriptional response are elucidated, showing a far greater role than previously suspected in the response to DNA replication stress.

Published
2017

6. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Wei-Ting Lu, Lykourgos-Panagiotis Zalmas, Konstantinos Evangelou, Ersilia Nigro, Vitor H. Teixeira, Mary Y. Wu, Robertus A.M. de Bruin, Ayse U. Akarca, Nicholas McGranahan, Michelle Dietzen, Panagiotis Galanos, Adam Pennycuick, Clare Puttick, Eric Santoni-Rugiu, Bryan Ngo, Jiri Bartek, William L. Brown, Sam M. Janes, Haoran Zhai, Deborah R. Caswell, Sebastijan Hobor, Cosetta Bertoli, Emilia L. Lim, Tim R. Fenton, Mariam Jamal-Hanjani, Reuben S. Harris, Roberto Bellelli, Brittany B. Campbell, Mihaela Angelova, Samuel F. Bakhoum, Eva Grönroos, Yue Zhao, Thomas B.K. Watkins, Robert E. Hynds, Vassilis G. Gorgoulis, Apolinar Maya-Mendoza, Maise Al Bakir, Charles Swanton, Teresa Marafioti, Andrew Rowan, Nnennaya Kanu, Michael Howell, Jirina Bartkova, Simon J. Boulton, Subramanian Venkatesan, Haiquan Chen, Venkatesan, S., Angelova, M., Puttick, C., Zhai, H., Caswell, D. R., Lu, W. -T., Dietzen, M., Galanos, P., Evangelou, K., Bellelli, R., Lim, E. L., Watkins, T. B. K., Rowan, A., Teixeira, V. H., Zhao, Y., Chen, H., Ngo, B., Zalmas, L. -P., Al Bakir, M., Hobor, S., Gronroos, E., Pennycuick, A., Nigro, E., Campbell, B. B., Brown, W. L., Akarca, A. U., Marafioti, T., Mary, Y. W., Howell, M., Boulton, S. J., Bertoli, C., Fenton, T. R., De Bruin, R. A. M., Maya-Mendoza, A., Santoni-Rugiu, E., Hynds, R. E., Gorgoulis, V. G., Jamal-Hanjani, M., Mcgranahan, N., Harris, R. S., Janes, S. M., Bartkova, J., Bakhoum, S. F., Bartek, J., Kanu, N., and Swanton, C.

Subjects
DNA Replication, Lung Neoplasms, viruses, Breast Neoplasms, Biology, Article, RC0254, Mice, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chromosomal Instability, Chromosome instability, medicine, Animals, Humans, APOBEC Deaminases, APOBEC Deaminase, QP506, Lung cancer, Gene, Mitosis, 030304 developmental biology, 0303 health sciences, Animal, DNA replication, Chromosome, Cancer, biochemical phenomena, metabolism, and nutrition, Cell cycle, medicine.disease, 3. Good health, Carcinoma, Ductal, Lung Neoplasm, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, Breast Neoplasm, Human
Abstract

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. Significance: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution. This article is highlighted in the In This Issue feature, p. 2355

Published
2020
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