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Defining how problematic DNA replication impacts on chromosome segregation

日期: 2018-10-26

生命科学学院2018年度秋季学期学术系列讲座
题目:Defining how problematic DNA replication impacts on chromosome segregation
讲座人: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
时间:2018年10月26日(星期五),13:00-15:00
地点:生命科学学院邓祐才报告厅
主持人:徐冬一


Abstract:

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.


Further reading:

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.

讲座二

题目:The impact of folate (叶酸) deficiency on the replication and segregation of the Fragile X trinucleotide repeat locus

Victoria A. Bjerregaard 1, Lorenza Garribba 1, Ivan Vogel1, Cynthia McMurray 2, and Ying Liu 1
1: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of
Copenhagen, Panum Institute, Copenhagen, Denmark

2: Lawrence Berkeley National Laboratory, Berkeley, USA


主讲人: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
Copenhagen, Denmark

摘要:Tri-nucleotide repeat sequences (TNRs) can be problematic when they exceed a crucial threshold length. For example, if the TNR lies within a crucial gene, it can lead to gene silencing that then causes severe diseases, including neurodegeneration (reviewed in [1]). We will present our current research on how TNR regions are replicated in S phase and segregated in mitosis using Fragile X syndrome (FXS) cells as a model. FXS is caused by a CGG repeat in the FRAXA region on chromosome X. The repeat lies in the non-coding (5’ UTR) region of the Mental Retardation Gene 1 (FMR1). This TNR expands from the pre-mutation allele length (55-200 units) to a full mutation (200-4000 units) almost exclusively through maternal transmission [2, 3]. Interestingly, the fully mutated FRAXA region is prone to break when the cells are exposed to folic acid (叶酸) deficient growth medium, which is a phenomenon akin to that seen with common fragile sites (CFSs) in response to DNA replication stress. Our results indicate that folic acid deficiency could induce fragility and missegregation of the FRAXA locus in mitosis. Current studies are aimed at deciphering the mechanism underlying the instability of the long CGG repeats under folic acid deficiency conditions.
References:
1. C.T. McMurray, Mechanisms of trinucleotide repeat instability during human development, Nature reviews. Genetics, 11 (2010) 786-799.
2. Y.H. Fu, D.P. Kuhl, A. Pizzuti, M. Pieretti, J.S. Sutcliffe, S. Richards, A.J. Verkerk, J.J. Holden, R.G. Fenwick, Jr., S.T. Warren, et al., Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox, Cell, 67 (1991) 1047-1058.
3. R.R. Sinden, V.N. Potaman, E.A. Oussatcheva, C.E. Pearson, Y.L. Lyubchenko, L.S. Shlyakhtenko, Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA, Journal of biosciences, 27 (2002) 53-65.

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