Telomere Loop Dynamics in Chromosome End Protection

Ly, David; Low, Ronnie Ren Jie; Frölich, Sonja; Bartolec, Tara K.; Kafer, Georgia R.; Pickett, Hilda A.; Gaus, Katharina; Cesare, Anthony J.

doi:10.1016/j.molcel.2018.06.025

Cited by 99 publications

(90 citation statements)

References 50 publications

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“…Phosphorylated NBS1 may bind to uncapped telomeres via MRE11 enabling ATM recruitment and activation ( Our data implicate SMCHD1 at the onset in the damage signaling cascade. We infer that SMCHD1 is not required for t-loop unwinding as its function at uncapped telomeres could be reinstated upon ATR activation ( Fig 6) and checkpoint kinases have not been implicated in t-loop unwinding (Van Ly et al, 2018). SMCHD1 promotes ATM activation as in its absence ATM is not efficiently phosphorylated and ATM pS1981 does not accumulate substantially in TIFs (Fig 7).…”

Section: Discussionmentioning

confidence: 96%

SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres

et al. 2020

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Structural maintenance of chromosomes flexible hinge domain‐containing protein 1 (SMCHD1) has been implicated in X‐chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD1 is required for DNA damage signaling and non‐homologous end joining (NHEJ) at unprotected telomeres. Co‐depletion of SMCHD1 and the shelterin subunit TRF2 reduced telomeric 3′‐overhang removal in time‐course experiments, as well as the number of chromosome end fusions. SMCHD1‐deficient cells displayed reduced ATM S1981 phosphorylation and diminished formation of γH2AX foci and of 53BP1‐containing telomere dysfunction‐induced foci (TIFs), indicating defects in DNA damage checkpoint signaling. Removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2‐depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2‐depleted cells due to defects in ATM‐dependent checkpoint signaling and that SMCHD1 mediates DNA damage response activation upstream of ATM phosphorylation at uncapped telomeres.

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Section: Discussionmentioning

confidence: 96%

SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres

et al. 2020

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“…Our data implicate SMCHD1 at the onset in the damage signaling cascade. We infer that SMCHD1 is not required for t-loop unwinding as its function at uncapped telomeres could be reinstated upon ATR activation ( Fig 5) and checkpoint kinases have not been implicated in t-loop unwinding (Van Ly et al, 2018). SMCHD1 promotes ATM activation as in its absence ATM is not efficiently phosphorylated and ATM pS1981 does not accumulate substantially in TIFs ( Fig 6).…”

Section: Discussionmentioning

confidence: 96%

“…TRF2 inhibits ATM signaling by several mechanisms involving its TRFH and hinge domains (Okamoto et al, 2013). The TRFH domain of TRF2 promotes formation of t-loops, which prevents exposure of the chromosome ends to the MRN complex not allowing ATM recruitment or activation (Doksani et al, 2013;Van Ly et al, 2018). In addition, the TRFH domain of TRF2 interacts at intact telomeres with a non-phosphorylated form of NBS1 preventing ATM activation (Rai et al 2017).…”

Section: Discussionmentioning

confidence: 99%

SMCHD1 Promotes ATM-dependent DNA Damage Signaling and Repair of Uncapped Telomeres

Vančevska

Pfeiffer

Feretzaki

et al. 2019

Preprint

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SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing protein 1) has been implicated in X-chromosome inactivation, imprinting and DNA damage repair. Mutations in SMCHD1 can also cause facioscapulohumoral muscular dystrophy. More recently, SMCHD1 has also been detected as component of telomeric chromatin. Here, we identify requirements of SMCHD1 for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 with TRF2 reduced the rate of 3' overhang removal in time course experiments and the number of telomere end fusions. In SMCHD1 deficient cells, the formation of ATM pS1981, gH2AX and 53BP1 containing telomere dysfunction induced foci (TIFs) were diminished indicating defects in checkpoint signaling. Strikingly, removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent DNA checkpoint signaling. SMCHD1 mediates DNA damage signaling activation upstream of ATM phosphorylation at uncapped telomeres.

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“…Instead, the telomere DDR resulted from activation of non-canonical mitotic telomere deprotection. Telomeres sequester the chromosome terminus within a t-loop, which when opened in a linear conformation exposes the DNA end as an ATM activating substrate 30 . We conclude human telomeres signal mitotic abnormalities induced by genomic DNA replication stress through the active alteration of telomere structure to activate DDR signalling.…”

Section: Discussionmentioning

confidence: 99%

“…During mitotic arrest in human cells, TRF2 dissociates from chromosome ends resulting in a telomere macromolecular structural change from telomere-loops (t-loops) to linear telomeres 28,30 . This exposes the chromosome end as an ATM substrate to activate the mitotic telomere DDR 30 .…”

Section: Lethal Replication Stress Induces Non-canonical Mitotic Telomentioning

confidence: 99%

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection

Masamsetti

Mak

Low

et al. 2018

Preprint

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Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPLdependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death promotes genome instability in replication stressed cells through diverse mechanisms depending upon how cell death is averted. These data demonstrate how replication stressinduced mitotic catastrophe signals cell death with implications for cancer treatment and genome instability.

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Telomere Loop Dynamics in Chromosome End Protection

Cited by 99 publications

References 50 publications

SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres

SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres

SMCHD1 Promotes ATM-dependent DNA Damage Signaling and Repair of Uncapped Telomeres

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection

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