Homeobox Telomere binding protein 1 (HOT1) as target to modulate telomere length
Telomeres consist of repetitive DNA sequences with associated proteins and represent the endpieces of chromosomes. In vertebrates the underlying DNA-sequence consists of six nucleotides (TTAGGG) that is repeated a couple of thousand times. Telomeres protect chromosomes from fusion or degradation and circumvent the ‘end replication problem’ thereby providing an important structural element for chromosomal stability. Nevertheless, during normal somatic cell divison cycles telomeres get constantly shortened which presumambly provides the molecular basis of the Hayflick limit at which mitotic senescence is triggered. However, a cellular process exists that counteracts telomere shortening. Telomerase is an enzyme capable to add further telomeric repeats at the end of the chromosomes. The enzyme is usually expressed at low levels in somatic cells but at high levels in germ and stem cells as well as in cancerous cells the latter exhibiting an unlimited ability to divide. On the other hand, abnormal telomere length i.e. pronounced telomere shortening can be correlated with a number of premature-aging syndromes like dyskeratosis congenital, aplastic anemia or idiopathic pulmonary fibrosis.
Scientists from the Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden together with scientists of the Max-Planck-Institute of Biochemistry in Munich described for the first time the combined interaction of Homeobox Telomere binding protein (HOT1; also HMBOX1 or TRF3) with the telomerase complex and telomeric repeats. It could be shown that HOT1 physically interacts with both entities and, in addition, also with Cajal body proteins suggesting that HOT1 mediates telomere-telomerase association in Cajal bodies. Overexpression and depletion of HOT1 in mammalian cells led to significant telomere lengthening and shortening, respectively, further stressing the role of HOT1 as a positive regulator of telomere length. Therefore, interference with the interaction of telomerase complex/telomeric repeats via HOT1 might provide an interesting target for the development of novel therapeutics.
An international application has been filed.