SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML Journal Article


Authors: Zhao, R.; Xu, M.; Yu, X.; Wondisford, A. R.; Lackner, R. M.; Salsman, J.; Dellaire, G.; Chenoweth, D. M.; O'Sullivan, R. J.; Zhao, X.; Zhang, H.
Article Title: SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML
Abstract: The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether-and if so, how-SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells. © 2024 Zhao et al.; Published by Cold Spring Harbor Laboratory Press.
Keywords: genetics; telomere; metabolism; dna repair; cell line; cell line, tumor; tumor cell line; sumo protein; sumoylation; sumo-1 protein; small ubiquitin-related modifier proteins; sumo; promyelocytic leukemia protein; rad52 protein; rad52 dna repair and recombination protein; sumo 1 protein; rad52; pml body; phase separation; pml protein, human; telomere homeostasis; humans; human; condensates; alt cancer
Journal Title: Genes and Development
Volume: 38
Issue: 13-14
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2024-07-01
Start Page: 614
End Page: 630
Language: English
DOI: 10.1101/gad.351667.124
PUBMED: 39038850
PROVIDER: scopus
PMCID: PMC11368244
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus
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  1. Xiaolan Zhao
    77 Zhao