TRIM28 Inhibits Alternative Lengthening of Telomeres
Telomeres are caps of repeated DNA sequences at the ends of chromosomes. A little of the telomere length is lost with each cell division. A somatic cell with short telomeres ceases replication, and usually self-destructs. All cancers must thus continually lengthen telomeres in order to engage in unfettered replication and growth. This makes interference in telomere lengthening an attractive strategy as the basis for a truly universal cancer therapy. A few research and development programs have this in mind, most of which are focused on the role of telomerase in telomere lengthening. There are alternative lengthening of telomeres (ALT) mechanisms which operate in some cancers, however. Dealing with telomerase alone solves only a majority of the problem. Unfortunately, finding an approach to interfering in ALT is an area of research with little support, and which is consequently moving very slowly. So it is always interesting to see news from that part of the field.
About 10-15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored.
Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA.
Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.