Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52

Jaewon Min, Woodring E Wright, Jerry W. Shay

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 mitotic DNA 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.

Original languageEnglish (US)
Pages (from-to)814-827
Number of pages14
JournalGenes & development
Volume33
Issue number13-14
DOIs
StatePublished - Jul 1 2019

Fingerprint

Telomere Homeostasis
Telomere
DNA
Leukemia
Cluster Analysis
Neoplasms
Telomerase
Ubiquitin
Saccharomyces cerevisiae
Maintenance
Phenotype

Keywords

  • ALT
  • biomolecular condensates
  • break-induced replication
  • MiDAS
  • phase separation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52. / Min, Jaewon; Wright, Woodring E; Shay, Jerry W.

In: Genes & development, Vol. 33, No. 13-14, 01.07.2019, p. 814-827.

Research output: Contribution to journalArticle

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