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Mechanisms that regulate the activities of TET proteins

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Abstract

The ten–eleven translocation (TET) family of dioxygenases consists of three members, TET1, TET2, and TET3. All three TET enzymes have Fe+2 and α-ketoglutarate (α-KG)-dependent dioxygenase activities, catalyzing the 1st step of DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Gene knockout studies demonstrated that all three TET proteins are involved in the regulation of fetal organ generation during embryonic development and normal tissue generation postnatally. TET proteins play such roles by regulating the expression of key differentiation and fate-determining genes via (1) enzymatic activity-dependent DNA methylation of the promoters and enhancers of target genes; and (2) enzymatic activity-independent regulation of histone modification. Interacting partner proteins and post-translational regulatory mechanisms regulate the activities of TET proteins. Mutations and dysregulation of TET proteins are involved in the pathogenesis of human diseases, specifically cancers. Here, we summarize the research on the interaction partners and post-translational modifications of TET proteins. We also discuss the molecular mechanisms by which these partner proteins and modifications regulate TET functioning and target gene expression. Such information will help in the design of medications useful for targeted therapy of TET-mutant-related diseases.

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Abbreviations

TET:

Ten–eleven translocation

α-KG:

α-Ketoglutarate

5mC:

5-Methylcytosine

5hmC:

5-Hydroxymethylcytosine

5fC:

5-Formylcytosine

5caC:

5-Carboxylcytosine

TFs:

Transcription factors

ARCH:

Age-related clonal hematopoiesis

MDS:

Myelodysplastic syndromes

AML:

Acute myeloid leukemia

ALL:

Acute lymphoblastic leukemia

DLBCLs:

Diffuse large B-cell lymphomas

PTCL:

Peripheral T-cell lymphoma

IFN-γ:

Interferon-γ

TNF-α:

Tumor necrosis factor-α

TIS:

Transcriptional initiation sites

DSBH:

Double-stranded beta-helix domain

TDG:

Thymine DNA glycosylase

BER:

Base excision repair

ES:

Embryonic stem cells

IDHs:

Isocitrate dehydrogenases

AP site:

Apyrimidinic site

AID:

Activation-induced cytidine deaminase

5hmU:

5-Hydroxymethyluracil

GC:

Germinal center

CSR:

Class-switch recombination

DSBs:

Double-strand breaks

PGCs:

Primordial germ cells

CGIs:

CpG islands

OGT:

O-linked GlcNAc transferase

SID:

Sin3A interacts with the Sin3-interaction domain

CoA:

Coactivators

PTM:

Post-translational modifications

AMPK:

AMP-activated protein kinase

C/EBPα:

CCAAT/enhancer-binding protein alpha

KLF4:

Kruppel-like factor-4

TFCP2l1:

Transcription factor CP2 like-1

YBX1:

Y box-binding protein-1

FOXK2:

Forkhead box protein K-2

KZF1:

DNA-binding protein Ikaros 1

NFIL3:

Nuclear factor interleukin-3-regulated protein

ATRX:

Alpha-thalassemia/mental retardation syndrome X-linked transcriptional regulator

CUX1:

Homeobox protein cut-like-1

YY2:

Yin and yang-2 transcription factor

IκBζ:

Inhibitory-kappa-B-zeta

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Funding

This work was supported by NIH grants R01 HL133560 and R01 CA223194 through Loyola University Chicago, as well as Loyola program development funds to Jiwang Zhang.

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  1. Kanak Joshi and Shanhui Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA

    Kanak Joshi, Peter Breslin S.J. & Jiwang Zhang

  2. School of Life Sciences, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, 730000, China

    Shanhui Liu

  3. Departments of Molecular/Cellular Physiology and Biology, Loyola University Medical Center and Loyola University Chicago, Chicago, IL, 60660, USA

    Peter Breslin S.J.

  4. Departments of Pathology and Radiation Oncology, Loyola University Medical Center, Maywood, IL, 60153, USA

    Jiwang Zhang

Authors
  1. Kanak Joshi
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  2. Shanhui Liu
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  3. Peter Breslin S.J.
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  4. Jiwang Zhang
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Contributions

Kanak Joshi and Shanhui Liu drafted the first version of this review. All of the authors contributed to the writing of this manuscript. Peter Breslin did the final editing. All authors read and approved the final manuscript.

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Correspondence to Jiwang Zhang.

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Joshi, K., Liu, S., Breslin S.J., P. et al. Mechanisms that regulate the activities of TET proteins. Cell. Mol. Life Sci. 79, 363 (2022). https://doi.org/10.1007/s00018-022-04396-x

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  • DOI: https://doi.org/10.1007/s00018-022-04396-x

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