TRF2 binds branched DNA to safeguard telomere integrity

Schmutz, Isabelle; Timashev, Leonid A.; Xie, Wei; Patel, Dinshaw J.; Lange, Titia de

doi:10.1038/nsmb.3451

Cited by 70 publications

(93 citation statements)

References 65 publications

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“…9). This indicates that TRF2ΔB cannot recruit the POT1 bound 3' end to the ds/ss-junction, consistent with the known function of basic domain in stabilizing the ds/ss three-way DNA junction 45 .…”

Section: Dynamic Movement Involves Discrete Stepssupporting

confidence: 69%

TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang

Paul

Liou

Cai

et al. 2020

Preprint

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Human telomeres are protected by shelterin components including POT1 and TRF2 but the molecular mechanism remains elusive. Here, we report an unexpected activity of POT1 in imparting conformational dynamics of the telomere overhang, even at a monomer level. Such POT1 induced overhang dynamics is greatly enhanced when TRF2 engages with the telomere duplex. Strikingly, TRF2 brings a POT1 bound overhang to the duplex and induces a stepwise movement up and down the axis of telomere duplex, thereby generating a highly dynamic loop formation. Interestingly, TRF2, but not TRF2ΔB, recruits POT1 bound overhang to the telomere duplex-single stranded junction by discrete steps of movement with a step size of TTAGGG. The same steps are observed regardless of the length of the POT1 bound overhang, suggesting a tightly regulated mechanism. Based on our results, we propose a plausible dynamic mechanism of t-loop formation coordinated by POT1 and TRF2.

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Section: Dynamic Movement Involves Discrete Stepssupporting

confidence: 69%

TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang

Paul

Liou

Cai

et al. 2020

Preprint

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“…Conversely, the Mre11/Rad50/Nbs1 (MRN) complex, which also plays a very early role in the signalling and repair of DSBs, has been suggested to require PARP1 for its recruitment to break sites (Haince et al, 2008;Bryant et al, 2009). However, there are also instances in which PARP1 activation must be actively suppressed, such as at telomeres, where the shelterin complex, and in particular TRF2, prevents PARP1 binding to avoid attempts of "repairing" telomeric DNA ends (Schmutz et al, 2017).…”

Section: Cellular Functions Of Adp-ribosylation Dna Damage Signallingmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD + as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.The PARP1 active site is formed between the catalytic domain (ART domain) and the helical domain (HD) Figure 1 -Schematic mechanism of ADP ribosylation reaction and the catalytic domain of DNA-dependant PARPs. A) A simplified overview of the (ADP)-ribosylation reactions catalysed by PARPs. The final products depend on the acceptor residue acting as a nucleophile (Nu, in blue). PARP1 active-site residues interacting with the ribose-nicotinamide moiety of NAD + are illustrated in orange. B) The NAD + (modelled based on the human PARP1 bound to benzamide adenine dinucleotide [PDB: 6BHV], carbon atoms in yellow) in an extended conformation, bound to the catalytic domain of human PARP1 (ART in cartoon, orange, [PDB: 6BHV]). The residues involved in the catalysis are presented as sticks. C) Superposed cartoon view of human PARP-1 ART domain (orange, [PDB: 6BHV]), PARP1 (light blue, [PDB: 5WS1]) and PARP2 (green, [PDB: 3KJD]) showing the structure of the entire catalytic domains (ART and HD). The modelled NAD + (in yellow) denotes the donor site, while a molecule of ADP (modelled by superimposing the structures of chicken PARP1 [PDB: 1A26] to the human PARP1 [PDB: 3KJD]) indicates the acceptor site. Donor loop (D-loop) and acceptor loop are labelled. D) Surface representation of human PARP1 [PDB: 3KJD] with NAD + modelled into the active site. The ribose group to be attacked is exposed to the solvent. ADP-ribose mechanisms and disease 3 ADP-ribose mechanisms and disease 13

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“…A conformational change from t-loops to linear telomeres with DDR activation at 36 hr could result from nucleolytic cleavage or degradation of the telomeric DNA and/or 3 0 overhang, resolution of t-loops into shortened linear telomeres and telomere circles (t-circles) (Schmutz et al, 2017), or t-loop unfolding, resulting in linear telomeres with no change in telomere length or overhang degradation. Separation of telomere restriction fragments on pulsed field gels corresponded with the super-resolution imaging data and verified telomere lengths were unaltered with 36 hr of 4-OHT treatment (Figures 2E, S4A, and S4B).…”

Section: Telomere Ddr Activation In Mefs Correlates With Linearized Tmentioning

confidence: 99%

Telomere Loop Dynamics in Chromosome End Protection

Low

Frölich

et al. 2018

Molecular Cell

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Telomeres regulate DNA damage response (DDR) and DNA repair activity at chromosome ends. How telomere macromolecular structure contributes to ATM regulation and its potential dissociation from control over non-homologous end joining (NHEJ)-dependent telomere fusion is of central importance to telomere-dependent cell aging and tumor suppression. Using super-resolution microscopy, we identify that ATM activation at mammalian telomeres with reduced TRF2 or at human telomeres during mitotic arrest occurs specifically with a structural change from telomere loops (t-loops) to linearized telomeres. Additionally, we find the TRFH domain of TRF2 regulates t-loop formation while suppressing ATM activity. Notably, we demonstrate that ATM activation and telomere linearity occur separately from telomere fusion via NHEJ and that linear DDR-positive telomeres can remain resistant to fusion, even during an extended G1 arrest, when NHEJ is most active. Collectively, these results suggest t-loops act as conformational switches that specifically regulate ATM activation independent of telomere mechanisms to inhibit NHEJ.

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TRF2 binds branched DNA to safeguard telomere integrity

Cited by 70 publications

References 65 publications

TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang

TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang

ADP-ribosylation: from molecular mechanisms to human disease

Telomere Loop Dynamics in Chromosome End Protection

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