@article{840d90ddf66349e2a0d96917149801aa,
title = "Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52",
abstract = "Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitoticDNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.",
keywords = "ALT, Biomolecular condensates, Break-induced replication, MiDAS, Phase separation",
author = "Jaewon Min and Wright, {Woodring E} and Shay, {Jerry W.}",
note = "Funding Information: We thank Michael K. Rosen (University of Texas Southwestern Medical Center) and Hongtao Yu (University of Texas Southwestern Medical Center) for sharing reagents and equipment, and Eunhee Choi (University of Texas Southwestern Medical Center) for flow cytometric analysis of the cell cycle and live-cell imaging. We also thank Roger R. Reddel (Children?s Medical Research Institute, Australia), Vincent G?li (Research Center of Cancerol-ogy of Marseille, France), J?r?me D?jardin (Institute of Human Genetics, France), Dirk Hockemeyer (University of California at Berkeley), and Shang Li (Duke-NUS, Singapore) for helpful discussions. This work was supported by AG01228 from the National Institute on Aging (to W.E.W. and J.W.S.) and the National Cancer Institute (NCI) T32 Cancer Research Training Program (CA124334 to J.M.). We also acknowledge the Harold Simmons NCI Designated Comprehensive Cancer Center Support grant (CA142543) and the Southland Financial Corporation Distinguished Chair in Geriatric Research (J.W.S. and W.E.W.). This work was performed in laboratories constructed with support from National Institutes of Health grant C06 RR30414. Funding Information: We thank Michael K. Rosen (University of Texas Southwestern Medical Center) and Hongtao Yu (University of Texas Southwestern Medical Center) for sharing reagents and equipment, and Eunhee Choi (University of Texas Southwestern Medical Center) for flow cytometric analysis of the cell cycle and live-cell imaging. We also thank Roger R. Reddel (Children{\textquoteright}s Medical Research Institute, Australia), Vincent G{\'e}li (Research Center of Cancerol-ogy of Marseille, France), J{\'e}r{\^o}me D{\'e}jardin (Institute of Human Genetics, France), Dirk Hockemeyer (University of California at Berkeley), and Shang Li (Duke-NUS, Singapore) for helpful discussions. This work was supported by AG01228 from the National Institute on Aging (to W.E.W. and J.W.S.) and the National Cancer Institute (NCI) T32 Cancer Research Training Program (CA124334 to J.M.). We also acknowledge the Harold Simmons NCI Designated Comprehensive Cancer Center Support grant (CA142543) and the Southland Financial Corporation Distinguished Chair in Geriatric Research (J.W.S. and W.E.W.). This work was performed in laboratories constructed with support from National Institutes of Health grant C06 RR30414. Publisher Copyright: {\textcopyright} 2019 Min et al.",
year = "2019",
month = jul,
doi = "10.1101/gad.324905.119",
language = "English (US)",
volume = "33",
pages = "814--827",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "13-14",
}