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An R-loop-initiated CSB-RAD52-POLD3 pathway suppresses ROS-induced telomeric DNA breaks

Jun Tan1,2, Meihan Duan3, Tribhuwan Yadav1,4

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.

Nucleic Acids Research
|November 29, 2019
PubMed

Insights

Reactive oxygen species (ROS) cause DNA damage at telomeres, leading to R-loop formation. This triggers a novel repair pathway involving CSB, RAD52, and POLD3 to protect telomeres.

Area of Science:

  • Genomics
  • DNA repair
  • Telomere biology

Background:

  • Reactive oxygen species (ROS) cause DNA damage, impacting genomic integrity.
  • Cellular responses to ROS-induced telomeric DNA damage are not well understood.

Purpose of the Study:

  • Investigate the mechanisms of cellular response to ROS-induced DNA damage at telomeres.
  • Identify key proteins and pathways involved in telomere protection against ROS.

Main Methods:

  • Analysis of R-loop accumulation at telomeres following ROS exposure.
  • Investigating the roles of TERRA, TRF2, CSB, and RAD52 in telomere damage response.
  • Assessing the impact of CSB and RAD52 on telomeric double-strand break (DSB) repair.
  • Examining the interaction between RAD52, CSB, POLD3, and DNA:RNA hybrids.

Main Results:

  • ROS-induced DNA damage at telomeres triggers R-loop accumulation dependent on TERRA and TRF2.
  • Both single-strand breaks (SSBs) and DSBs contribute to R-loop induction.
  • CSB and RAD52 are recruited to damaged telomeres and are essential for DSB repair.
  • RAD52 facilitates DSB repair via interaction with CSB and POLD3, enabling break-induced replication (BIR).

Conclusions:

  • ROS-induced telomeric R-loops activate a novel CSB-RAD52-POLD3-mediated BIR pathway for DSB repair.
  • This pathway is crucial for protecting telomeres from ROS-induced damage.
  • ROS-induced SSBs can indirectly lead to DSBs and also promote DSB repair through R-loop induction.

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