Associate Professor - Promotion Programme
Blegdamsvej 3, 2200 København N.
Primary fields of research
Liu group aims to understand 1) the measures cells use to counteract replication stress caused by either internal factors (i.e. oncogene activation), or external factors (i.e. folate deficiency), and, 2) why some regions in the genome are particularly susceptible to those factors (e.g. common or rare fragile sites). Specifically, we focus on the two areas shown below. We employ techniques in the fields of cellular and molecular biology, cytogenetics, biochemistry, advanced microscope imaging, whole genome sequencing and mass spectrometry based proteomics.
1) The analysis of mechanisms underlying MiDAS
It is well established that incomplete replication can cause a delay in chromatin condensation that leads to the ‘expression’ of common fragile sites (CFSs) [1, 2]. CFSs are hot spots for deletions and chromosome rearrangements in cancer . We previously have taken part in the discovery of a process called mitotic DNA synthesis (MiDAS) that operates in mitosis is a strategy used by human cells to rescue the incomplete replication at those loci, particularly in cancers cells that has elevated replication stress (RS) [4-7] (Figure 1). Particularly, both RAD52 and POLD3 play a crucial role in MiDAS. Our recent findings demonstrate that: i) RTEL1, a DNA helicase, can prevent the accumulation of G-quadruplex-associated R-loops at difficult-to-replicate loci including CFSs in the human genome in S phase, and can facilitate MiDAS in M phase ; ii) both translesion polymerases and replication replication polymerase delta play a crucial role in completing MiDAS . In addition, using a BioID strategy , we have identified a panel of factors that could potentially work closely with POLD3 when cells are challenged with RS. We are now investigating the functions of these factors and their relevance to MiDAS.
2) The analysis of folate deficiency induced genome instability
Folate deficiency is known to be associated with a diverse range of human disorders including fetal neural tube defects, age-associated dementia, infertility, and some type of cancers. Intriguingly, folate deficiency is known to cause the expression of group of rare fragile sites, all of which contain long stretch of CGG simple repeats. The most well studied locus of this kind is called FRAXA that is associated with Fragile X syndrome (FXS). Using FXS cells as a model, we demonstrated that folate deprivation triggers the extensive missegregation and aneuploidy of chromosome X , and MiDAS at the FRAXA locus via the break-induced DNA replication (BIR) that requires the SLX1/SLX4 endonuclease complex, the RAD51 recombinase and POLD3 . Recently, based on a combination of bioinformatic and cellular biology analysis, we demonstrated that folate deficiency could cause the abnormal segregation of a region with CG-Rich trinucleotide repeats on human chromoso
- Helmrich, A., M. Ballarino, and L. Tora, Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes. Molecular Cell, 2011. 44(6): p. 966-977.
- Letessier, A., G.A. Millot, S. Koundrioukoff, A.M. Lachages, N. Vogt, R.S. Hansen, B. Malfoy, O. Brison, and M. Debatisse, Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature, 2011. 470(7332): p. 120-3.
- Richards, R.I., Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet, 2001. 17(6): p. 339-45.
- Bjerregaard, V.A., O. Ozer, I.D. Hickson, and Y. Liu, The Detection and Analysis of Chromosome Fragile Sites. Methods Mol Biol, 2018. 1672: p. 471-482.
- Garribba, L., W. Wu, O. Ozer, R. Bhowmick, I.D. Hickson, and Y. Liu, Inducing and Detecting Mitotic DNA Synthesis at Difficult-to-Replicate Loci. Mechanisms of DNA Recombination and Genome Rearrangements: Intersection between Homologous Recombination, DNA Replication and DNA Repair, 2018. 601: p. 45-58.
- Minocherhomji, S., S. Ying, V.A. Bjerregaard, S. Bursomanno, A. Aleliunaite, W. Wu, H.W. Mankouri, H. Shen, Y. Liu, and I.D. Hickson, Replication stress activates DNA repair synthesis in mitosis. Nature, 2015. 528(7581): p. 286-90.
- Ren, L., L. Chen, W. Wu, L. Garribba, H. Tian, Z. Liu, I. Vogel, C. Li, I.D. Hickson, and Y. Liu, Potential biomarkers of DNA replication stress in cancer. Oncotarget, 2017. 8(23): p. 36996-37008.
- Wu, W., R. Bhowmick, I. Vogel, O. Ozer, F. Ghisays, R.S. Thakur, E. Sanchez de Leon, P.H. Richter, L. Ren, J.H. Petrini, I.D. Hickson, and Y. Liu, RTEL1 suppresses G-quadruplex-associated R-loops at difficult-to-replicate loci in the human genome. Nat Struct Mol Biol, 2020. 27(5): p. 424-437.
- Wu, W., S.A. Barwacz, R. Bhowmick, K. Lundgaard, M.M. Goncalves Dinis, M. Clausen, M.T. Kanemaki, and Y. Liu, Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells. Nat Commun, 2023. 14(1): p. 706.
- Roux, K.J., D.I. Kim, M. Raida, and B. Burke, A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. Journal of Cell Biology, 2012. 196(6): p. 801-810.
- Bjerregaard, V.A., L. Garribba, C.T. McMurray, I.D. Hickson, and Y. Liu, Folate deficiency drives mitotic missegregation of the human FRAXA locus. Proc Natl Acad Sci U S A, 2018.
- Garribba, L., V.A. Bjerregaard, M.M. Goncalves Dinis, O. Ozer, W. Wu, D. Sakellariou, J. Pena-Diaz, I.D. Hickson, and Y. Liu, Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells. Proc Natl Acad Sci U S A, 2020. DOI: 10.1073/pnas.1921219117.
- Garribba, L., I. Vogel, M. Lerdrup, M.M. Goncalves Dinis, L. Ren, and Y. Liu, Folate Deficiency Triggers the Abnormal Segregation of a Region With Large Cluster of CG-Rich Trinucleotide Repeats on Human Chromosome 2. Front Genet, 2021. 12: p. 695124.
2010 - present, teach Molecular Biology and Genetics in the first year of the Human Biology Master program, a Copenhagen Master of Excellence program (one of the 12 elite Master programs sponsored by the Danish Ministry of Science, Technology and Innovation).
Give lectures and supervise in lab and bioinformatic practical courses. Lectures include ‘Introduction to Genetics’, ‘Cancer Genetics’, ‘Introduction to Bioinformatics, and ‘Cell Cycle’. The lab course is focused on cloning and protein expression. The bioinformatic course is focused on database search.
2011 – 2015: the organiser of Health Aging IARU summer school
2015 – present: teach ‘DNA Replication, Repair and Gene Regulation’ in the Medical Cell and Tissue Biology course for first year Medicine / Odontology students.