Compromised Telomeric Heterochromatin Promotes ALTernative Lengthening of Telomeres

doi:10.1016/j.trecan.2016.02.003

Trends in Cancer

Volume 2, Issue 3, March 2016, Pages 114-116

https://doi.org/10.1016/j.trecan.2016.02.003 Get rights and content

Alternative lengthening of telomeres (ALT) is an enigmatic process that allows certain cancers to maintain telomeres in the absence of telomerase. ALT cancers are frequently defective for ATRX/DAXX, a chaperone complex that deposits histone variant H3.3 at telomeres. We propose that mutations in alpha thalassemia-mental retardation syndrome X-linked (ATRX)/death-domain associated protein (DAXX) prime ALT activation by disrupting telomeric heterochromatin.

Section snippets

Mutations in ATRX/DAXX Correlate with Activation of ALT

Telomeres are stretches of repetitive DNA that protect the chromosome ends. Replication of linear chromosomes is constrained by lagging-strand synthesis and never progresses to completion, a process dubbed the ‘end-replication problem’. As a result, telomeres are shortened after each round of cell division and this progressive telomere attrition eventually leads to cellular senescence. Cancer cells escape this proliferative constraint by activating one of two distinct mechanisms of telomere

Disruption of Telomeric Heterochromatin is Permissive to ALT Activation

To maintain integrity, telomeres must be protected from being recognised as DNA double-strand breaks by the DNA repair machinery. To achieve this, telomeric DNA adopts a unique structural conformation known as a T-loop, where a single-stranded overhang is looped backwards and invades the preceding double-stranded telomere to form an enclosed structure [9]. In addition, telomeres are bound by a specialised Shelterin complex, which inhibits unlicensed DNA repair at telomeric ends and regulates

Acknowledgements

We thank The Norwegian Cancer Society and Research Council of Norway (P.C.), the Australia Research Council (ARC) Future Fellowship Award, and Cure Brain Cancer Australia (L.H.W.) for funding.

References (12)

J.D. Henson et al.
Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers
FEBS Lett.
(2010)
A.D. Goldberg
Distinct factors control histone variant H3.3 localization at specific genomic regions
Cell
(2010)
H.P. Voon
ATRX plays a key role in maintaining silencing at interstitial heterochromatic loci and imprinted genes
Cell Rep.
(2015)
L.H. Wong
ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells
Genome Res.
(2010)
Y. Jiao
DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors
Science
(2011)
C.M. Heaphy
Altered telomeres in tumors with ATRX and DAXX mutations
Science
(2011)

There are more references available in the full text version of this article.

Cited by (16)

Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity
2021, Translational Oncology
Citation Excerpt :
ATRX is now a diagnostic marker for gliomas due to its frequency and distinguishing characteristics, as nearly 30% of younger glioma patients have an ATRX mutation [6]. ATRX loss is also necessary but not sufficient for the Alternative-Lengthening of Telomeres pathway, which occurs in 10–15% of tumors [7]. ATRX has been implicated in a number of DNA damage response (DDR) pathways, including replication stress response [8–10], homologous recombination (HR) [11,12] and non-homologous end joining (NHEJ) [13].
Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.
Chromatin Bottlenecks in Cancer
2019, Trends in Cancer
Citation Excerpt :
The ATRX chromatin-remodeling complex normally assembles nucleosomes at telomeres using the histone H3.3 variant, which may be necessary to restore nucleosomes displaced by aberrant G-quadruplex DNA structures, replication fork stalling, and transcription at telomeres. Without ATRX, telomeric DNA becomes exposed and recombinogenic [44,45]. Although this suffices to circumvent the telomeric bottleneck, ALT is less common in neuroblastomas than telomerase-mediated telomere extension because telomeric recombination also results in prolonged DNA damage response activation, genomic damage (chromothripsis), and sensitivity to replication stress [39].
Cancer accounts for ∼9 million deaths per year worldwide, predominantly affecting adults. Adult malignancies are usually examined after extensive clonal evolution and carry many mutations, obscuring the individual contributions of these alterations to oncogenesis. By contrast, pediatric cancers often contain few mutations, many of which cause defects in chromatin-associated proteins. We explore here the roles that chromatin plays in oncogenesis. We highlight how the developmental regulation of cell proliferation genes and the degradation of chromosome ends are two major bottlenecks in the evolution of malignant cells, and point to a third bottleneck where epigenomic dysfunction triggers expression of tumor-suppressor genes, limiting the development of aggressive and metastatic features in tumors. We also identify opportunities for chromatin-based therapies.
The Chromatin Remodeler ATRX: Role and Mechanism in Biology and Cancer
2023, Cancers
Telomere Transcription in MLL-Rearranged Leukemia Cell Lines: Increased Levels of TERRA Associate with Lymphoid Lineage and Are Independent of Telomere Length and Ploidy
2023, Biomedicines
Chromatin mutations in pediatric high grade gliomas
2023, Frontiers in Oncology
DAXX-ATRX regulation of p53 chromatin binding and DNA damage response
2022, Nature Communications

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Trends in Cancer

ForumCompromised Telomeric Heterochromatin Promotes ALTernative Lengthening of Telomeres

Section snippets

Mutations in ATRX/DAXX Correlate with Activation of ALT

Disruption of Telomeric Heterochromatin is Permissive to ALT Activation

Acknowledgements

FEBS Lett.

Cell

Cell Rep.

ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells

Genome Res.

DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

Science

Altered telomeres in tumors with ATRX and DAXX mutations

Science

Forum
Compromised Telomeric Heterochromatin Promotes ALTernative Lengthening of Telomeres