題目：Defining how problematic DNA replication impacts on chromosome segregation
講座人：Ian D. Hickson, PhD FMedSci FRS,
Director of the DNRF Center for Chromosome Stability, and Professor of Molecular Aging,
Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark
Ultra-fine bridges (UFBs) are thin threads of DNA that connect the separating sister DNA masses in anaphase. They cannot be stained with DNA dyes and do not contain histones, making their detection problematic and dependent on immunofluorescence for associated proteins such as PICH or BLM. Nevertheless, they are very abundant, and are a feature of all anaphases. UFBs arise from specific loci that are characterized by the unusual sequence or structure: most notably, centromeres, the rDNA, telomeres and common fragile sites (CFSs). We are conducting a detailed analysis of two aspects of UFB biology: modeling the association of proteins to UFBs in vitro using optical tweezers, and investigating how unresolved UFBs affect cell division. In addition, through analysis of the underlying basis of UFB formation in human cells, we identified that CFSs and telomeres are still undergoing DNA synthesis in early mitosis in a process we term MiDAS. MiDAS depends upon a subset of homologous recombination factors, such as RAD52, but not RAD51/BRCA2, and appears to be a form of break-induced DNA replication. Inhibition of MiDAS leads to major chromosome segregation abnormalities. The latest progress on these projects will be presented.
1. Chan, K-L., North, P.S. and Hickson, I.D. (2007) BLM is required for faithful chromosome segregation and its localization defines a class of ultra-fine anaphase bridges. EMBO J., 26, 3397-3409.
2. Chan, K-L., Palmai-Pallag, T., Ying, S. and Hickson, I.D. (2009) Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nature Cell Biology 11, 753-760.
3. Biebricher, A., Hirano, S., Enzlin, J.H., Wiechens, N., Streicher, W.W., Wang, L.H.C., Nigg, E.A., Owen-Hughes, T., Liu, Y., Peterman, E., Wuite, G.J.L. and Hickson, I.D. (2013) PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. Molecular Cell 51, 691-701.
4. Ying, S., Minocherhomji, S., Chan, K.L., Palmai-Pallag, T., Chu, W.K., Wass, T., Mankouri, H.W., Liu, Y. and Hickson, I.D. (2013) MUS81 promotes common fragile site expression. Nature Cell Biol. 15, 1001-1006.
5. Minocherhomji, S., Ying, S., Bjerregaard, V.A., Bursomanno, S., Aleliunaite, A., Wu, W., Mankouri, H.W., Shen, H., Liu, Y. and Hickson, I.D. (2015) Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286-290.
6. Nielsen, C.F., Huttner, D., Bizard, A.H., Hirano, S., Li, T-N., Palmai-Pallag, T., Bjerregaard, V.A., Liu, Y., Nigg, E.A., Wang, L.H-C. and Hickson, I.D. (2015) PICH promotes sister chromatid disjunction in mitosis: evidence of functional co-operation with topoisomerase II. Nature Communications 6, 8962.
7. Bhowmick, R., Minocherhomji, S. and Hickson, I.D. (2016) RAD52 facilitates mitotic DNA synthesis following replication stress. Molecular Cell 64, 1117-1126.
8. Sarlós, K., Biebricher, A.S., Bizard, A.H., Bakx, J.A.M., Ferrete-Bonastre, A.G., Modesti, M., Paramasivam, M., Yao, Q., Peterman, E.J.G., Wuite, G.J.L. and Hickson, I.D. (2018) Reconstitution of anaphase DNA bridge recognition and disjunction in vitro. Nature Structural and Molecular Biology 25, 868-876.
題目：The impact of folate (葉酸) deficiency on the replication and segregation of the Fragile X trinucleotide repeat locus
2: Lawrence Berkeley National Laboratory, Berkeley, USA
主講人：Ying Liu, MD PhD
Principal Investigator in the DNRF Center for Chromosome Stability, and Associate
Professor in Department of Cellular and Molecular Medicine, University of