DNA:RNA hybrids at telomeres - when it is better to be out of the (R) loop

FEBS J. 2018 Jul;285(14):2552-2566. doi: 10.1111/febs.14464. Epub 2018 Apr 20.


R-loops (RLs) are three-stranded nucleic acid structures that contain a DNA:RNA hybrid and a displaced DNA strand. Genomic regions with GC skew and a G-rich transcript are particularly prone to form RLs. RLs play important physiological roles in cells; however, when present at abnormally high levels, they may threaten genome stability. The perfect GC skew of telomeric repeats and the discovery of telomeric repeat-containing RNA (TERRA), a long noncoding transcript that consists of the G-rich telomeric sequence, make telomeric sequences the perfect candidates for generating RLs. Indeed, in the past 5 years, telomere R-loops (TRLs) have been demonstrated in Saccharomyces cerevisiae, Trypanosoma brucei, and human cells. The presence of TRLs in normal human cells that transcribe low levels of TERRA, suggests a physiological role for these nucleic structures in telomere maintenance. Abnormally enhanced TERRA transcription, as found in several human pathological conditions, leads to high TRL levels and various cellular outcomes, depending on the recombinogenic capabilities of the cells. Study of TRLs in various organisms highlights the necessity for tight regulation of these structures, which can switch from beneficial to detrimental under different conditions. Here, we review the current state of knowledge on TRLs, describe several means by which TRLs are regulated, and discuss how findings from yeast are relevant to human pathological scenarios in which TRLs are deregulated.

Keywords: ATRX; DNA:RNA hybrid; GC skew; ICF syndrome; R-loop; TERRA; alternative pathway; recombination; subtelomere; telomere.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Base Composition
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • Face / abnormalities*
  • Face / pathology
  • Gene Expression Regulation
  • Genome*
  • Genomic Instability
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / pathology
  • Nucleic Acid Conformation
  • Nucleic Acid Hybridization*
  • Primary Immunodeficiency Diseases
  • RNA, Long Noncoding / chemistry*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Telomere / chemistry*
  • Telomere / metabolism
  • Telomere Homeostasis
  • Trypanosoma brucei brucei / genetics
  • Trypanosoma brucei brucei / metabolism


  • RNA, Long Noncoding
  • DNA

Supplementary concepts

  • Immunodeficiency syndrome, variable