A significant portion of human cancers utilize a recombination-based pathway, alternative lengthening of telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (telomeric ALT in situ localization screen) to identify genes that either promote or inhibit ALT activity. Screening over 1,000 genes implicated in DNA transactions, TAILS reveals both well-established and putative ALT modulators. Here, we present the validation of factors that promote ALT, such as the nucleosome-remodeling factor CHD4 and the chromatin reader SGF29, as well as factors that suppress ALT, including the RNA helicases DExD-box helicase 39A/B (DDX39A/B), the replication factor TIMELESS, and components of the chromatin assembly factor CAF1. Our data indicate that defects in histone deposition significantly contribute to ALT-associated phenotypes. Based on these findings, we demonstrate that pharmacological treatments can be employed to either exacerbate or suppress ALT-associated phenotypes.
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Identification of modulators of the ALT pathway through a native FISH-based optical screen.
Cell Rep
December 2024
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:
A significant portion of human cancers utilize a recombination-based pathway, alternative lengthening of telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (telomeric ALT in situ localization screen) to identify genes that either promote or inhibit ALT activity. Screening over 1,000 genes implicated in DNA transactions, TAILS reveals both well-established and putative ALT modulators.
View Article and Find Full Text PDFIdentification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen.
bioRxiv
November 2024
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
A significant portion of human cancers utilize a recombination-based pathway, Alternative Lengthening of Telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (Telomeric ALT Localization Screen), to identify genes that either promote or inhibit ALT activity. Screening over 1000 genes implicated in DNA transactions, TAILS revealed both well-established and novel ALT modulators.
View Article and Find Full Text PDFPolyubiquitinated PCNA triggers SLX4-mediated break-induced replication in alternative lengthening of telomeres (ALT) cancer cells.
Nucleic Acids Res
October 2024
Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Korea.
Replication stresses are the major source of break-induced replication (BIR). Here, we show that in alternative lengthening of telomeres (ALT) cells, replication stress-induced polyubiquitinated proliferating cell nuclear antigen (PCNA) (polyUb-PCNA) triggers BIR at telomeres and the common fragile site (CFS). Consistently, depleting RAD18, a PCNA ubiquitinating enzyme, reduces the occurrence of ALT-associated promyelocytic leukemia (PML) bodies (APBs) and mitotic DNA synthesis at telomeres and CFS, both of which are mediated by BIR.
View Article and Find Full Text PDFALTering Cancer by Triggering Telomere Replication Stress through the Stabilization of Promoter G-Quadruplex in .
ACS Chem Biol
July 2024
Department of Biophysics, Bose Institute, EN 80, Sector V, Bidhan Nagar, Kolkata 700091 West Bengal, India.
Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer.
View Article and Find Full Text PDFOrphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.
Nucleic Acids Res
June 2024
Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11529, Taiwan.
Article Synopsis
- Orphan nuclear receptors (NRs) like COUP-TF1 and others are linked to telomerase-negative cancers that use an alternative mechanism (ALT) to maintain their telomeres, but their exact role in activating ALT is unknown.
- The study shows that when these orphan NRs are attached to telomeres in human fibroblasts, they trigger the formation of specific structures (APBs) and activate ALT processes, indicating that they can induce ALT from scratch.
- Overexpression of orphan NRs enhances ALT activity, while their removal decreases it, showing their critical role in promoting ALT, potentially offering a target for new therapies using agents like arsenic trioxide to inhibit ALT in cancer cells.
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