2. Academic Validation
  3. Identification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen

Identification of Novel Modulators of the ALT Pathway Through a Native FISH-Based Optical Screen

  • bioRxiv. 2024 Nov 15:2024.11.15.623791. doi: 10.1101/2024.11.15.623791.
Benura Azeroglu 1,  Simran Khurana 2,  Shih-Chun Wang 3,  Gianna M Tricola 1,  Shalu Sharma 2,  Camille Jubelin 1,  Ylenia Cortolezzis 3 4,  Gianluca Pegoraro 5,  Kyle M Miller 3,  Travis H Stracker 2,  Eros Lazzerini Denchi 1
Affiliations

Affiliations

  • 1 Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • 2 Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
  • 4 Department of Medicine, Università degli Studi di Udine, Udine, Italy.
  • 5 High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
PMID: 39605432 DOI: 10.1101/2024.11.15.623791
Abstract

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 1000 genes implicated in DNA transactions, TAILS revealed both well-established and novel ALT modulators. We have identified new 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 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.

Keywords

ALT; DDX39A; histone deposition; ssTelo; telomeres.

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