People

Faculty

Manor Haim, Professor Emeritus

Phone:  (972)-4-8293456

Research area 1

Research Area 1:

1. Telomeres and telomerase.

Telomeres are specialized DNA-RNA-protein complexes at the ends of linear eukaryotic chromosomes. The telomeres are required for maintenance and proper segregation of the chromosomes. In most eukaryotic organisms, the telomeric DNA consists of short repeats. In human cells and in cells of other mammals the double-stranded telomeric DNA consists of d(TTAGGG)n.d(CCCAAT)n repeats. At the ends of these repeats, the G-rich strand forms a single-stranded 3'-extension, d(TTAGGG)n. Telomerase is a special type of reverse transcriptase, whose function is to elongate the single-stranded telomeric extensions. Its major two components are a catalytic protein subunit designated TERT and an RNA subunit designated TER, which includes a short template sequence that encodes the telomeric DNA repeats. In addition, the telomerase contains several accessory proteins that play significant roles in the assembly and the activity of the enzyme. A simple diagram illustrated here in Fig. 1 shows how the telomerase synthesizes multiple telomeric repeats by using the RNA template sequence that contains just one and a half repeats of the complementary sequence.          

Most types of human cells do not contain active telomerase in amounts that are sufficient for telomeric DNA synthesis. Hence, multiple divisions of these cells result in shortening of the telomeres until they reach a minimal length that causes cessation of cell division, or cell death. In contrast, cancer cells in most tumors contain active telomerase that extends their telomeres. Therefore, cancer cells do not stop dividing and are said to be immortalized. One important prediction of these observations is that in cancer patients, telomerase inhibitors should not cause substantial damage to normal cells, but should block the growth of tumors by causing shortening of the telomeres in the tumor cells and a consequent cessation of their division. Therefore, such inhibitors should be useful as selective anti-cancer drugs. Some of the symptoms of aging and ageing related diseases also result from telomere shortening in certain types of cells and consequent death of such cells in aged individuals. The presence and the activity of telomerase should affect these aging processes. Hence, studies of telomerase biochemistry will be helpful in the design of strategies for treatment of ageing-related diseases, as well as the development of anti-cancer drugs.     

We are studying the mechanism of telomeric DNA synthesis by telomerase. So far, our research focused on the interactions between the enzyme components and the elongating DNA chains in active telomerase complexes. We have used for this research the telomerase of the ciliate Tetrahymena thermophila, which shares several key properties with the human enzyme, and is a particularly suitable model system for mechanistic studies. The results of these studies have been described in several articles that are included in a list of selected publications from our laboratory, which are presented below.

 

Figure 1: Schematic illustration of the synthesis of multiple repeats of single-stranded telomeric DNA in a reaction catalyzed by the Tetrahymena telomerase.

The template is the sequence indicated in white, which is a part of the RNA subunit of the telomerase. The protein components of the enzyme are schematically represented by the blue ellipse. The single-stranded telomeric DNA (yellow) aligns with the template and is elongated by the enzyme. The elongation stops at the end of the template. Then, both the active site of the enzyme and the DNA end are translocated to the beginning of the template. Subsequently, the next repeat is synthesized, and so on. There is also a so called anchor site (indicated schematically by a red rectangle), which keeps the DNA attached to the enzyme during translocation.

References:

1. Greider,C.W. and Blackburn,E.H. (1987), Cell 51, 887-898.

2. Greider,C.W. (1991),  Mol. Cell Biol. 11, 4572-4580.

3. Lingner,J., Hughes,T.R., Shevchenko,A., Mann,M., Lundblad,V., and Cech,T.R. (1997), Science 276, 561-567.

4. Min,B. and Collins,K. (2009), Mol. Cell 36, 609-619.