Alternative lengthening of telomeres mediated by mitotic DNA synthesis engages breakinduced replication processes

Jaewon Min, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by breakinduced replication, similar to type II ALT survivors in Saccharomyces cerevisiae. Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.

Original languageEnglish (US)
Article numbere00226-17
JournalMolecular and cellular biology
Volume37
Issue number20
DOIs
StatePublished - Oct 1 2017

Keywords

  • ALT
  • Cyclin E
  • G quadruplex
  • MiDAS
  • R-loop
  • RAD51
  • RAD52
  • SMC5/6
  • TIMELESS
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Alternative lengthening of telomeres mediated by mitotic DNA synthesis engages breakinduced replication processes'. Together they form a unique fingerprint.

Cite this