The MUS81 endonuclease is essential for telomerase negative cell proliferation

Zeng, Sicong; Yang, Qin

doi:10.4161/cc.8.14.9149

Cited by 18 publications

(15 citation statements)

References 33 publications

(54 reference statements)

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“…Previously, it was shown that MUS81 localizes to APBs and that its depletion results in increased telomere loss and reduced telomere recombination (Zeng et al., 2009, Zeng and Yang, 2009). Since both EME1 and EME2 localize to APBs in ALT cells (data not shown), we determined the levels of telomere loss by quantitative fluorescent in situ hybridization (Q-FISH) analysis, and the frequency of telomere recombination by chromosome orientation FISH (CO-FISH), after depletion of MUS81, EME1, or EME2.…”

Section: Resultsmentioning

confidence: 99%

MUS81-EME2 Promotes Replication Fork Restart

2014

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SummaryReplication forks frequently stall at regions of the genome that are difficult to replicate or contain lesions that cause replication blockage. An important mechanism for the restart of a stalled fork involves endonucleolytic cleavage that can lead to fork restoration and replication progression. Here, we show that the structure-selective endonuclease MUS81-EME2 is responsible for fork cleavage and restart in human cells. The MUS81-EME2 protein, whose actions are restricted to S phase, is also responsible for telomere maintenance in telomerase-negative ALT (Alternative Lengthening of Telomeres) cells. In contrast, the G2/M functions of MUS81, such as the cleavage of recombination intermediates and fragile site expression, are promoted by MUS81-EME1. These results define distinct and temporal roles for MUS81-EME1 and MUS81-EME2 in the maintenance of genome stability.

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Section: Resultsmentioning

confidence: 99%

MUS81-EME2 Promotes Replication Fork Restart

2014

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“…37 Other human telomerase-associated nucleases might also associate with hTERT-mediated telomere shortening. 24,25,38 Future studies will determine whether these factors are required for hTERT-mediated telomere-shortening process.…”

Section: Discussionmentioning

confidence: 99%

“…S5), which is consistent with previous reports. 24,25 In fact, expression of hTERT reduced the number of telomere signal-free ends in all the cell lines tested. Our observations are in agreement with previous reports that overexpression of hTERT in human primary cells leads to continued cell growth and extended life span in the absence of a DNA damage response.…”

Section: Upregulation Of Endogenous Htert Maintains Small Tlv In Primmentioning

confidence: 99%

“…hTERT-mediated telomere shortening increases t-circle formation T-circle formation has been shown to involve the telomere recombination mechanism, 13,[24][25][26] and the increase in t-circles in ALT+ cells is considered a by-product of removed long telomeres. 11 Expression of hTERT in SAOS2 cells increased t-circles as measured by the 2D gel assay (Fig.…”

Section: Upregulation Of Endogenous Htert Maintains Small Tlv In Primmentioning

confidence: 99%

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Telomerase enzymatic component hTERT shortens long telomeres in human cells

et al. 2014

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“…Experiments were performed as described [39;41;42]. Briefly, for conventional immunofluorescence microscopy, the cells were examined with a Zeiss Axioskop fluorescence microscope equipped with a CCD camera (Ontario, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers

et al. 2014

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Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance.

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The MUS81 endonuclease is essential for telomerase negative cell proliferation

Cited by 18 publications

References 33 publications

MUS81-EME2 Promotes Replication Fork Restart

MUS81-EME2 Promotes Replication Fork Restart

Telomerase enzymatic component hTERT shortens long telomeres in human cells

Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers

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