AI Article Synopsis

  • Inappropriate homology-directed repair (HDR) of telomeres can lead to severe genome instability due to catastrophic telomere loss and abnormal chromosome fusions.* -
  • The TRF2-RAP1 complex plays a critical role in preventing such issues by inhibiting RAD51-facilitated D-loop formation and ultimately blocking harmful HDR at telomeres.* -
  • TRF2 works with the BLM helicase to unwind D-loops and prevents telomere end resection that would lead to overhangs necessary for RAD51 activity, highlighting distinct molecular pathways that protect telomeres.*

Article Abstract

Inappropriate homology-directed repair (HDR) of telomeres results in catastrophic telomere loss and aberrant chromosome fusions, leading to genome instability. We have previously shown that the TRF2-RAP1 heterodimer protects telomeres from engaging in aberrant telomere HDR. Cells lacking the basic domain of TRF2 and functional RAP1 display HDR-mediated telomere clustering, resulting in the formation of ultrabright telomeres (UTs) and massive chromosome fusions. Using purified proteins, we uncover three distinct molecular pathways that the TRF2-RAP1 heterodimer utilizes to protect telomeres from engaging in aberrant HDR. We show mechanistically that TRF2-RAP1 inhibits RAD51-initiated telomeric D-loop formation. Both the TRF2 basic domain and RAP1-binding to TRF2 are required to block RAD51-mediated homology search. TRF2 recruits the BLM helicase to telomeres through its TRFH domain to promote BLM-mediated unwinding of telomere D-loops. In addition, TRF2-RAP1 inhibits BLM-DNA2-mediated 5' telomere end resection, preventing the generation of 3' single-stranded telomere overhangs necessary for RAD51-dependent HDR. Importantly, cells expressing BLM mutants unable to interact with TRF2 accumulate telomere D-loops and UTs. Our findings uncover distinct molecular mechanisms coordinated by TRF2-RAP1 to protect telomeres from engaging in aberrant HDR.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381343PMC
http://dx.doi.org/10.1093/nar/gkae642DOI Listing

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