Chromosome Maintenance Group
Group Leader: Dr Kazunori Tomita
Why can cancer cells propagate indefinitely? A clue can be found at chromosome ends, telomeres. Telomeres are indispensable for chromosome stability in propagating cells, and the length of telomeres defines the number of times a cell divides. Elucidating the systems that regulate, and the functions of, telomeres are essential for our understanding of cancer cell immortality as well as cellular ageing.
Our cells harbour all the information required for the construction of our body and life cycle. These data are ‘encoded’ by long linear DNA molecules, called chromosomes. The physical end-regions of the chromosome, called telomeres, play critical roles in the maintenance of chromosomes.
Stresses from both outside and inside cells can cause breaks in chromosomes. These broken DNA sites are repaired by DNA damage surveillance and repair systems. Although chromosome ends are similar in structure to the ends of the DNA at break sites, telomeres are able to avoid inappropriate repair, which if left un-checked, would cause chromosome end-to-end fusions. Despite its essental function in chromosome maintenance, chromosomes lose telomeric DNA progressively with each round of cell division. So as not to lose chromosome protection, shortened telomeres elicit a checkpoint dependent arrest of the cell cycle, resulting in cellular senescence (ageing) [Fig. 1].
Cancer cells escape this programmed cell scenesence by activating a protein, telomerase. Telomerase counteracts the DNA loss at short telomeres by replenishing telomeric DNA. Using this protein, cancer cells are able to maintain chromosome ends, and therefore continue dividing [Fig. 1]. However, cancer cells somehow maintain relatively short telomeres, compared to normal cells. Such short telomeres or unprogrammed telomere maintenance can lead to uneven chromosome segregation [Fig. 2], which causes malignant progression. We aim to understand how telomeres are maintained and how they act to maintain chromosomes through successive cell divisions.
To address these issues, we primarily employ fission yeast as a model system. Fission yeast telomeres have a similar structure and function to human telomeres and are also maintained by telomerase. Using this model organism allows an intricate genetic approach to be taken to uncover mechanisms at the molecular level. Studies from fission yeast will greatly contribute to the understanding of telomerase action in normal and cancer cells in humans. We hope this will lead to the development of advanced cancer treatments and techniques to aid with diagnosis.
We are interested in how telomeres utilize the DNA damage response and cell cycling factors to maintain telomeres and participate in chromosome maintenance and cell cycle regulation. The following aims are currently being investigated.
1. Molecular mechanisms underlying telomerase recruitment
To extend telomeric DNA, telomerase first needs to contact the telomere complex. We are investigating the molecular link between telomeres and telomerase, and exploring how this connection is regulated. A key factor is likely to be the telomeric protein Ccq1 and its binding protein Tpz1. Ccq1 was found to be a telomerase recruiter that connects the main telomere protection proteins (Pot1-Tpz1) and telomerase, and is required for the association of telomerase to telomeres (Tomita & Cooper 2008).
2. Dynamics of short telomeres
Telomerase acts preferentially at shortened telomeres. Hence, there should be certain differences between long and short telomeres. Intriguingly, Ccq1 is the protein that not only recruits telomerase, but is also involved in silencing of the DNA damage checkpoint at short telomeres (Tomita & Cooper 2008). A number of DNA damage response and DNA replication proteins in fact participate in telomere maintenance and telomerase regulation. We aim to understand why telomerase prefers to associate with short telomeres.
3. Telomere function and regulation in meiotic prophase
Telomeres function not only in maintaining intact chromosomal ends but are also directly involved in meiotic progression. Organisms diversify and propagate their genomic information throughout successive generations through the process of meiosis. Understanding the process of meiosis is important, as defects of meiosis are a major reason for miscarriages in humans. In the early stage of meiotic prophase, telomeres gather near the microtubule organizing-center (MTOC) to form the so-called ‘bouquet’ structure [Fig. 3]. Failure to form the chromosomal bouquet results in aberrant spindle poles and meiotic spindle defects (Tomita & Cooper 2007; Tomita et. al. 2013). Notably, termination of the bouquet stage is likely to be regulated [Fig. 4]. We hypothesize that telomeric heterochromatin coordinates the progression of chromosomal events during meiotic prophase with maturation of the MTOC through bouquet formation/termination. Revealing telomere functions in meiotic prophase would benefit to disclose a central function of telomeres, and may contribute to our understanding of telomeres in cancer, as malignant cells are likely to activate inappropriate telomeric functions.
Kazunori Tomita, PhD
- Siân Pearson
- Christine Armstrong, PhD
- Hanna Amelina, PhD
- Vera Moiseeva, PhD
Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle.
Gravells P, Tomita K, Booth A, Poznansky J, Porter ACG. Human Molecular Genetics 2013; 22(14):2842-5. Pubmed
A single internal telomere tract ensures meiotic spindle formation.
Tomita K, Bez C, Fennell A, Cooper JP. EMBO Rep. 2013; 14(3):252-260. Pubmed
Fission yeast Ccq1 is telomerase recruiter and local checkpoint controller. Tomita K, Cooper JP. Genes Dev. 2008 Dec 15;22(24):3461-74. Pubmed
The telomere bouquet controls the meiotic spindle. Tomita K, Cooper JP. Cell. 2007 Jul 13;130(1):113-26. Pubmed
The meiotic chromosomal bouquet: SUN collects flowers. Tomita K, Cooper JP. Cell. 2006 Apr 7;125(1):19-21. Pubmed
Fission yeast Dna2 is required for generation of the telomeric single-strand overhang. Tomita K, Kibe T, Kang HY, Seo YS, Uritani M, Ushimaru T, Ueno M. Mol Cell Biol. 2004 Nov;24(21):9557-67. Pubmed
Competition between the Rad50 complex and the Ku heterodimer reveals a role for Exo1 in processing double-strand breaks but not telomeres. Tomita K, Matsuura A, Caspari T, Carr AM, Akamatsu Y, Iwasaki H, Mizuno K, Ohta K, Uritani M, Ushimaru T, Yoshinaga K, Ueno M. Mol Cell Biol. 2003 Aug;23(15):5186-97. Pubmed