TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation

Chuanle Wang,Yan Huang,Zhou Songyang

doi:10.1186/s13578-021-00660-y

Abstract

BackgroundAbout 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.ResultsHere 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.ConclusionsOur 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.

Highlights

Telomeres are special structures at the ends of eukaryotic chromosomes, which is composed of TTAGGGrepeat sequence and a protein complex called "telosome" or "shelterin" [1, 2]
Telomere chromatin immunoprecipitation (ChIP) assays showed that TRIM28 is located on telomeres, and TRIM28 is preferentially located on telomeres of alternative lengthening of telomeres (ALT) -dependent U2OS cells compared to telomerase positive HTC75 cells (Fig. 1B, C)
Plasmids that express TRIM28 with GST tag and telosome/shelterin subunits with HA-Flag double tags were co-transfected into HEK293T cells

Summary

Introduction

Telomeres are special structures at the ends of eukaryotic chromosomes, which is composed of TTAGGGrepeat sequence and a protein complex called "telosome" or "shelterin" [1, 2]. 85–90% of tumor cells extend telomeres by activating telomerase, while 10–15% of them utilize telomerase-independent mechanism called the alternative lengthening of telomeres (ALT) [11]. ALT is a homologous recombination (HR)-directed telomere synthesis pathway [12]. There are obvious differences in telomere length between ALT cells and telomerase positive cells, which may be caused by the rapid deletion or lengthening of telomeres. The chromosomal telomere length is highly heterogeneous [13]. About 10–15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. The mechanism of ALT needs to be further explored

Methods

Results

Conclusion