The basic N-terminal domain of TRF2 limits recombination endonuclease action at human telomeres

Saint-Léger, Adélaïde; Koelblen, Mélanie; Civitelli, Livia; Bah, Amadou; Djerbi, Nadir; Giraud-Panis, Marie-Josèphe; Londoño-Vallejo, Arturo; Ascenzioni, Fiorentina; Gilson, Éric

doi:10.4161/cc.29422

Cited by 48 publications

(56 citation statements)

References 54 publications

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“…[30][31][32] It has been also reported that As 2 O 3 treatment leads to damage to telomeres. 33 We then studied whether Mus81 sumoylation was involved in DNA damage responses after exposure to metal toxins including arsenic and chromium .…”

Section: Compromised Dna Damage Response In Cells Expressing Mus81-5rmentioning

confidence: 96%

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Yang

et al. 2017

Cell Cycle

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Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As 2 O 3 , an environmental metal toxicant, upregulated overall modifications of many cellular proteins by SUMO2/3. Sumoylated proteins from arsenic-treated cells constitutively expressing His 6 -SUMO2 were pulled down by Ni-IDA resin under denaturing conditions. Mass spectrometric analysis revealed over 100 proteins that were potentially modified by sumoylation. Mus81, a DNA endonuclease involved in homologous recombination repair, was among the identified proteins whose sumoylation was increased after treatment with As 2 O 3. We further showed that K10 and K524 were 2 lysine residues essential for Mus81 sumoylation. Moreover, we demonstrated that Mus81 sumoylation is important for normal mitotic chromosome congression and that cells expressing SUMO-resistant Mus81 mutants displayed compromised DNA damage responses after exposure to metal toxins such as Cr(VI) and arsenic.

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Section: Compromised Dna Damage Response In Cells Expressing Mus81-5rmentioning

confidence: 96%

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Yang

et al. 2017

Cell Cycle

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“…Using the SLX4–SLX1 complex, TRF2 has been proposed to control telomere-length homeostasis by regulating the trimming mechanism, in which very long telomeres are shortened by t-loop excision. TRF2 TRFH -dependent recruitment of SLX4 would induce t-loop excision at very long telomeres, whereas the basic domain of TRF2 would inhibit SLX4 and therefore stabilize t loops at normal telomeres 43,47,49 . Of note, although mouse SLX4 is involved in persistent t-loop excision upon RTEL1 depletion, it does not bear the TRF2-binding motif and does not localize to mouse telomeres 46 .…”

Section: The End Protection Problem: Inhibition Of the Ddrmentioning

confidence: 99%

“…50). The basic domain of TRF2 also inhibits resolvase activities at telomeres, thereby promoting telomere replication and stabilizing t loops 48,49 . Rad51 is also recruited to telomeres by BRCA2 during G2, when it has been suggested to play a role in facilitating telomere replication 51 , thus again demonstrating the complex interaction of the HR machinery with telomeres during and after replication.…”

Section: The End Protection Problem: Inhibition Of the Ddrmentioning

confidence: 99%

Complex interactions between the DNA-damage response and mammalian telomeres

Arnoult

Karlseder

2015

Nat Struct Mol Biol

171

159

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Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the ‘end-protection problem’ by inhibiting multiple DNA damage–response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation.

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“…21,26 TRF2 also contributes to the synthesis of functional 3 0 G-overhangs, which are required for folding telomeres into t-loop structures, 27,28 to the unwinding of t-loops, 10 and to the maintenance of telomere integrity following the topological stress encountered during DNA replication in S phase. 29,30 In addition, TRF2 prevents excess accumulation of long non-coding telomeric repeat-containing RNAs, TERRA, 31 which are transcribed from subtelomeric regions and function as structural components of telomeres. [32][33][34] TRF2 acts as a protein 'hub' to recruit shelterin and nonshelterin proteins through its N-terminal GAR domain and its central TRFH dimerization domain ( Table 1).…”

Section: Nuclear Role Of Trf2mentioning

confidence: 99%

The long and the short of TRF2 in neurogenesis

et al. 2016

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Gene expression patterns change dramatically during neuronal development. Proliferating cells, including neural stem cells (NSCs), express telomere repeat-binding factor 2 (TRF2), a nuclear protein that associates with telomeric proteins, DNA, and RNA telomeres. In NSCs TRF2 also binds to the transcription regulator REST to facilitate repression of numerous neuron-specific genes, thereby keeping the NSCs in a selfrenewing state. Upon neuronal differentiation, TRF2 levels decline, REST-regulated neuronal genes are derepressed, and a short isoform of TRF2 arises (TRF2-S) which localizes in the cytoplasm, associates with different subsets of proteins and transcripts, and mobilizes axonal G-rich mRNAs. We recently identified two RNA-binding proteins, HNRNPH1 and H2 (referred to jointly as HNRNPH due to their high homology), which mediate the alternative splicing of an exon required for the expression of full-length TRF2. As HNRNPH levels decline during neurogenesis, TRF2 abundance decreases and TRF2-S accumulates. Here, we discuss the shared and unique functions of TRF2 and TRF2-S, the distinct subcellular compartment in which each isoform resides, the subsets of proteins and nucleic acids with which each interacts, and the functional consequences of these ribonucleoprotein interactions. This paradigm illustrates the dynamic mechanisms through which splicing regulation by factors like HNRNPH enable distinct protein functions as cells adapt to developmental programs such as neurogenesis.

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The basic N-terminal domain of TRF2 limits recombination endonuclease action at human telomeres

Cited by 48 publications

References 54 publications

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Complex interactions between the DNA-damage response and mammalian telomeres

The long and the short of TRF2 in neurogenesis

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