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

Overview

Journal bioRxiv

Date 2024 Nov 28

PMID 39605432

Authors

Benura Azeroglu

Simran Khurana

Shih-Chun Wang

Gianna M Tricola

Shalu Sharma

Camille Jubelin

Ylenia Cortolezzis

Gianluca Pegoraro

Kyle M Miller

Travis H Stracker

Eros Lazzerini Denchi

Affiliations

Soon will be listed here.

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 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.

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