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

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Abstract

Background

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.

Results

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.

Conclusions

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13578-021-00660-y.

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Most cited references 60

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Telomeres shorten during ageing of human fibroblasts.

C Harley, A Futcher, C Greider (1990)

The terminus of a DNA helix has been called its Achilles' heel. Thus to prevent possible incomplete replication and instability of the termini of linear DNA, eukaryotic chromosomes end in characteristic repetitive DNA sequences within specialized structures called telomeres. In immortal cells, loss of telomeric DNA due to degradation or incomplete replication is apparently balanced by telomere elongation, which may involve de novo synthesis of additional repeats by novel DNA polymerase called telomerase. Such a polymerase has been recently detected in HeLa cells. It has been proposed that the finite doubling capacity of normal mammalian cells is due to a loss of telomeric DNA and eventual deletion of essential sequences. In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. Here, we show that the amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. It is not known whether this loss of DNA has a causal role in senescence.

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Alternative lengthening of telomeres: models, mechanisms and implications.

Anthony J Cesare, Roger R. Reddel (2010)

Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10-15% of cancers - including some with particularly poor outcome - it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT.

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The telomere syndromes.

Mary Armanios, Elizabeth H Blackburn (2012)

There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.

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Author and article information

Contributors

Yan Huang:

ORCID: http://orcid.org/0000-0001-5466-7714

huangy336@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): Cell Biosci

Journal ID (iso-abbrev): Cell Biosci

Title: Cell & Bioscience

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-3701

Publication date (Electronic): 30 July 2021

Publication date PMC-release: 30 July 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 149

Affiliations

[1 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, , Sun Yat-Sen University, ; Guangzhou, 510275 China

[2 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, 510120 China

[3 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, , Baylor College of Medicine, ; One Baylor Plaza, Houston, TX 77030 USA

[4 ]GRID grid.508040.9, Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), ; Guangzhou, 510005 China

Author information

Yan Huang http://orcid.org/0000-0001-5466-7714

Article

Publisher ID: 660

DOI: 10.1186/s13578-021-00660-y

PMC ID: 8325274

PubMed ID: 34330324

SO-VID: 46a45f13-9024-4d54-beda-c7ac551a471a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 January 2021

Date accepted : 15 July 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81871109

Award Recipient : Yan Huang

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: trim28/kap1,setdb1,alternative lengthening of telomere phenotypes,heterochromatin

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: trim28/kap1, setdb1, alternative lengthening of telomere phenotypes, heterochromatin

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

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Abstract

Background

Results

Conclusions

Supplementary Information

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Claudins

Most cited references 60

Telomeres shorten during ageing of human fibroblasts.

Alternative lengthening of telomeres: models, mechanisms and implications.

The telomere syndromes.

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Contributors

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