Scientific Reports (Feb 2021)

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity

  • Yang Mei,
  • Zhong Deng,
  • Olga Vladimirova,
  • Nitish Gulve,
  • F. Brad Johnson,
  • William C. Drosopoulos,
  • Carl L. Schildkraut,
  • Paul M. Lieberman

DOI
https://doi.org/10.1038/s41598-021-82406-x
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 14

Abstract

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Abstract Telomere dysfunction causes chromosomal instability which is associated with many cancers and age-related diseases. The non-coding telomeric repeat-containing RNA (TERRA) forms a structural and regulatory component of the telomere that is implicated in telomere maintenance and chromosomal end protection. The basic N-terminal Gly/Arg-rich (GAR) domain of telomeric repeat-binding factor 2 (TRF2) can bind TERRA but the structural basis and significance of this interaction remains poorly understood. Here, we show that TRF2 GAR recognizes G-quadruplex features of TERRA. We show that small molecules that disrupt the TERRA-TRF2 GAR complex, such as N-methyl mesoporphyrin IX (NMM) or genetic deletion of TRF2 GAR domain, result in the loss of TERRA, and the induction of γH2AX-associated telomeric DNA damage associated with decreased telomere length, and increased telomere aberrations, including telomere fragility. Taken together, our data indicates that the G-quadruplex structure of TERRA is an important recognition element for TRF2 GAR domain and this interaction between TRF2 GAR and TERRA is essential to maintain telomere stability.