FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway

Root, Heather; Larsen, Andrew; Komosa, Martin; Ren, Li; Bazett-Jones, David P.; Meyn, M. Stephen

doi:10.1093/hmg/ddw175

Cited by 40 publications

(36 citation statements)

References 94 publications

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“…Depletion of FANCD2 alone, however, does not trigger the ALT phenotype, indicating the involvement of additional factors. Increased telomeric DNA content as a consequence of telomere elongation and tSCEs in FANCD2-depleted cells occur through a RAD51independent mechanism, which one could hypothesize is in agreement with the notion of a RAD51-independent, RAD52mediated ALT process (62). Additionally, the recent observation of MiDAS at telomeres, has also been shown to be RAD52dependent and SLX4-dependent but RAD51-independent (22,63).…”

Section: Break Induced Replication Drives Alt Telomere Synthesissupporting

confidence: 82%

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

et al. 2020

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Achieving replicative immortality is a crucial step in tumorigenesis and requires both bypassing cell cycle checkpoints and the extension of telomeres, sequences that protect the distal ends of chromosomes during replication. In the majority of cancers this is achieved through the enzyme telomerase, however a subset of cancers instead utilize a telomerase-independent mechanism of telomere elongation-the Alternative Lengthening of Telomeres (ALT) pathway. Recent work has aimed to decipher the exact mechanism that underlies this pathway. To this end, this pathway has now been shown to extend telomeres through exploitation of DNA repair machinery in a unique process that may present a number of druggable targets. The identification of such targets, and the subsequent development or repurposing of therapies to these targets may be crucial to improving the prognosis for many ALT-positive cancers, wherein mean survival is lower than non-ALT counterparts and the cancers themselves are particularly unresponsive to standard of care therapies. In this review we summarize the recent identification of many aspects of the ALT pathway, and the therapies that may be employed to exploit these new targets.

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Section: Break Induced Replication Drives Alt Telomere Synthesissupporting

confidence: 82%

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

et al. 2020

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“…It has also been previously reported that large telomeric foci contain extrachromosomal telomeric DNAs (49). These extrachromosomal telomeric DNAs can form large telomeric foci with chromosomal DNAs in response to DNA replication stress in a BLM helicase-dependent manner (50). Intriguingly, telomeres were clustered as observed by the visualization of large telomeric foci in Saos2 cells.…”

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confidence: 54%

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

Min

Wright

Shay

2017

Molecular and Cellular Biology

163

205

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Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.

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“…FANCD2 loss increased C circles in ALT cells, consistent with previous reports (Supplemental Figs. S3A,B, S4A;Fan et al 2009;Root et al 2016). Nascent C-circle generation was highest in G2-arrested cells and decreased dramatically as cells entered mitosis in both control and FANCD2-depleted cells (Supplemental Fig.…”

Section: Rad52 Is Recruited To Alt Telomeres To Resolve Replication Smentioning

confidence: 95%

RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening

et al. 2019

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Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability.

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FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway

Cited by 40 publications

References 94 publications

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening

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