Chromosome Maintenance Group
Group Leader: Dr Kazunori Tomita
Why can cancer cells propagate indefinitely? A hint can be found at chromosome ends, telomeres. Telomeres are indispensable for chromosome stability in propagating cells, and the length of telomeres define the number of times a cell divides. Elucidating systems and functions of telomeres are essential for our understanding of cancer cell immortality as well as cellular aging.
Our cells harbour all information required for 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, yet these broken DNA sites are recovered by DNA damage surveillance and repair systems. Although chromosome ends harbour similar structure to the DNA ends of the broken site, telomeres protect against these systems to avoid inappropriated repair, which if left un-checked, would cause chromosome end-to-end fusions. Despite its essencial 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 cell propagation cycle, resulting in cellular senescence (aging) [Fig 1].
Cancer cells escape this programmed cell scenesence by activating a protein, telomerase. Telomerase counter-acts 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 short telomeres, comparing 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 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’s and are also maintained by telomerase. Using this model organism allows an intricate genetics approach, a technique useful to uncover mechanisms in 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 the diagnosis.
We are interested in how telomeres utilize the DNA damage response and cell cycling factors to maintain telomeres and participate in 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 explore how this connection is regulated. A key factor is likely to be the telomeric protein Ccq1. Ccq1 was found to be a telomerase recruiter that connects a main telomere protection protein (Pot1) 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. Thus, we hypothesize that Ccq1 activity as a telomerase recruiter is triggered by the recognition of the DNA damage checkpoint at short telomeres.
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