Telomere damage induces internal loops that generate telomeric circles

Mazzucco, Giulia; Huda, Armela; Galli, Maria Grazia; Piccini, Daniele; Giannattasio, Michele; Pessina, Fabio; Doksani, Ylli

doi:10.1038/s41467-020-19139-4

Cited by 39 publications

(41 citation statements)

References 40 publications

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“…However, recent evidence suggests that C-circles are likely the byproducts of BITS during the repair and restart of the stalled or collapsed replication forks at damaged telomeres [27,42]. Telomeric repeats neighboring DNA damage sites are thought to form internal loops (I-loops), which are excised to form ECTRs, such as C-circles [43]. C-circles are regarded as the most sensitive, specific, and quantitative biomarker of the ALT activity [41,44].…”

Section: Commonly Used Alt Biomarkersmentioning

confidence: 99%

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

MacKenzie

Watters

et al. 2021

Cancers

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Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis and cancer treatment. In this review, we first discuss how the activation of this pathway is determined. We then provide up-to-date statistics on the cancers ALT activity is detected. Additionally, we discussed the relationship between ALT positivity and prognosis as well as the pathogenetics of the ALT positive cancers. Finally, we evaluated the pre-clinical and clinical investigation of potential therapy for ALT cancers.Abstract: Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.

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Section: Commonly Used Alt Biomarkersmentioning

confidence: 99%

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

MacKenzie

Watters

et al. 2021

Cancers

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“…T-circles function in recombination-dependent maintenance pathways by serving as templates for the rolling circle synthesis of telomere DNA. This may be the same case for animal and plant t-circles ( 20 , 69 ). It is estimated that 15% of human immortalized cell lines may maintain telomere length through alternative lengthening of telomeres ( 70 ).…”

Section: Telomere and Rdna Copy Number Maintenancementioning

confidence: 74%

Extrachromosomal Circular DNA: Category, Biogenesis, Recognition, and Functions

Cao

Wang

et al. 2021

Front. Vet. Sci.

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Extrachromosomal circular DNA (eccDNA), existing as double-stranded circular DNA, is derived and free from chromosomes. It is common in eukaryotes but has a strong heterogeneity in count, length, and origin. It has been demonstrated that eccDNA could function in telomere and rDNA maintenance, aging, drug resistance, tumorigenesis, and phenotypic variations of plants and animals. Here we review the current knowledge about eccDNA in category, biogenesis, recognition, and functions. We also provide perspectives on the potential implications of eccDNA in life science.

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“…Both BIR pathways are involved in APB formations during ALT cell DNA synthesis, but only the RAD52-independent BIR pathway is critical for C-circle formation [ 18 ]. Telomeric DNA break-induced replication fork collapse and telomere damage-induced internal loops are both involved in C-circle formation [ 73 , 74 ]. In SUN1-depleted cells, both the APB formation and C-circle levels were increased.…”

Section: Discussionmentioning

confidence: 99%

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

Yang

Hsieh

Sun

2021

Aging

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Telomere length homeostasis is essential for maintaining genomic stability and cancer proliferation. Telomerase-negative cancer cells undergo recombination-mediated alternative lengthening of telomeres. Telomeres associate with the nuclear envelope through the shelterin RAP1 and nuclear envelope SUN1 proteins. However, how the associations between telomeres and the nuclear envelope affect the progression of telomere recombination is not understood. Here, we show that telomere anchorage might inhibit telomere-telomere recombination. SUN1 depletion stimulates the formation of alternative lengthening of telomeres-associated promyelocytic leukemia bodies in ALT cells. In contrast, overexpression of a telomere-nuclear envelope-tethering chimera protein, RAP1-SUN1, suppresses APB formation. Moreover, inhibition of this nuclear envelope attachment alleviates the requirement of TOP3α for resolving the supercoiling pressure during telomere recombination. A coimmunoprecipitation assay revealed that the SUN1 N-terminal nucleoplasmic domain interacts with the RAP1 middle coil domain, and phosphorylation-mimetic mutations in RAP1 inhibit this interaction. However, abolishing the RAP1-SUN1 interaction does not hinder APB formation, which hints at the existence of another SUN1-dependent telomere anchorage pathway. In summary, our results reveal an inhibitory role of telomere-nuclear envelope association in telomere-telomere recombination and imply the presence of redundant pathways for the telomere-nuclear envelope association in ALT cells.

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Telomere damage induces internal loops that generate telomeric circles

Cited by 39 publications

References 40 publications

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

Extrachromosomal Circular DNA: Category, Biogenesis, Recognition, and Functions

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

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