Azeroglu Benura, Khurana Simran, Wang Shih-Chun, Tricola Gianna M, Sharma Shalu, Jubelin Camille, Cortolezzis Ylenia, Pegoraro Gianluca, Miller Kyle M, Stracker Travis H, Denchi Eros Lazzerini
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
bioRxiv. 2024 Nov 15:2024.11.15.623791. doi: 10.1101/2024.11.15.623791.
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.
很大一部分人类癌症利用一种基于重组的途径——端粒替代延长（ALT）来延长端粒。为了更深入地了解这一途径，我们开发了一种基于高通量成像的筛选方法，名为TAILS（端粒ALT定位筛选），以鉴定促进或抑制ALT活性的基因。通过筛选1000多个与DNA交易相关的基因，TAILS揭示了既定的和新的ALT调节剂。我们已经鉴定出促进ALT的新因子，如核小体重塑因子CHD4和染色质阅读器SGF29，以及抑制ALT的因子，包括RNA解旋酶DDX39A/B、复制因子TIMELESS和染色质组装因子CAF1的组分。我们的数据表明，组蛋白沉积缺陷显著导致了ALT相关表型。基于这些发现，我们证明可以采用药物治疗来加重或抑制ALT相关表型。
