Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway

Laud, Purnima R.; Multani, Asha S.; Bailey, Susan M.; Wu, Ling; Ma, Jin; Kingsley, Charles V.; Lebel, Michel; Pathak, Sen; DePinho, Ronald A.; Chang, Sandy

doi:10.1101/gad.1321305

Cited by 175 publications

(166 citation statements)

References 52 publications

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“…The results presented in this paper also support earlier findings and provide further evidence for the role of BRCA1 in telomere homeostasis. Similarly to cells lacking BLM and WRN, proteins affected in Bloom and Werner syndrome patients (Salk et al, 1985; Laud et al, 2005), we have shown that BRCA1 defective cells harbor high frequencies of T‐SCEs (Figs. 1A and 3A).…”

Section: Discussionsupporting

confidence: 69%

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Kargaran

Yasaei

Anjomani-Virmouni

et al. 2016

Genes Chromosomes & Cancer

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Telomeres are specialized structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALTs) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C‐circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 69%

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Kargaran

Yasaei

Anjomani-Virmouni

et al. 2016

Genes Chromosomes & Cancer

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“…In the first case, it is known that the WRN protein interacts with several telomere proteins and unwinds a telomeric D-loop structure (35). Furthermore, the loss of WRN function facilitates the activation of the alternative lengthening of telomeres mechanism, which may engender cancer-relevant chromosomal aberrations and tumor formation in mouse models (36). Interestingly, alternative lengthening of telomeres is commonly observed in sarcomas, where we have also observed WRN hypermethylation and which are characteristic of patients with WS.…”

Section: Discussionmentioning

confidence: 75%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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“…Telomerase-independent telomere maintenance that results in telomeres of normal length has been reported for primary and lymphoma cells from mouse telomerase RNA mutants (33), although other studies have revealed long and heterogeneous telomeres in mouse tumors derived in the context of telomerase deficiency (34,35). One immortalized human cell line, C3-cl6, maintained short and homogeneous telomeres in the absence of telomerase (10).…”

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

Cheng¹,

Shtessel

Brady

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Canonical telomere repeats at chromosome termini can be maintained by a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Human cancers that survive via ALT can exhibit long and heterogeneous telomeres, although many telomerase-negative tumors possess telomeres of normal length. Here, we report that Caenorhabditis elegans telomerase mutants that survived via ALT possessed either long or normal telomere lengths. Most ALT strains displayed end-to-end chromosome fusions, suggesting that critical telomere shortening occurred before or concomitant with ALT. ALT required the 9-1-1 DNA damage response complex and its clamp loader, HPR-17. Deficiency for the POT-2 telomere binding protein promoted ALT in telomerase mutants, overcame the requirement for the 9-1-1 complex in ALT, and promoted ALT with normal telomere lengths. We propose that telomerase-deficient human tumors with normal telomere lengths could represent a mode of ALT that is facilitated by telomere capping protein dysfunction. PROTECTION OF TELOMERES-2 | telomere maintenanceT elomeres are tandem repeat tracts that cap the ends of linear chromosomes and erode with each cell cycle because of the inability of canonical DNA polymerases to completely replicate chromosome termini (1). However, the ribonucleoprotein telomerase combats this erosion by adding de novo telomeric repeats via reverse transcription (2). Progressive telomere shortening during proliferation of human somatic cells can trigger senescence, which serves as a major tumor suppression mechanism (3). Bypass of senescence and further cell proliferation leads to critical telomere shortening and crisis, resulting in high levels of cell death due to chromosome instability (4). Many tumors overcome this proliferation barrier by activating expression of the telomerase reverse transcriptase. The remaining 10-15% of human tumors do not possess telomerase activity (5, 6).S. cerevisiae strains deficient for telomerase can survive with long and heterogeneous telomeres composed of amplified telomere repeats (type II survivors) (7,8). Analogous to type II survivors, long and heterogeneous telomeres occur in almost all in vitro immortalized cell lines and tumor-derived cells lines that are telomerase-negative (9-11). Furthermore, extensive analysis of telomerase activity and telomere length from primary human tumor samples has revealed that certain telomerase-negative tumors possess long and heterogeneous telomeres, defined as alternative lengthening of telomeres (ALT) tumors (9). However, the majority (81/108) of primary tumors lacking telomerase activity have telomeres of normal lengths (9,(12)(13)(14)(15). This subset of telomerase-negative tumors may have become neoplastic before exhausting their telomere repeat reserves (9, 16). Alternatively, these tumors could have evolved via the same telomeredriven crisis events that give rise to ALT tumors, followed by activation of a distinct form of ALT that maintains telomeres of apparently normal lengths (9).Homologous recombinatio...

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Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway

Cited by 175 publications

References 52 publications

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

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