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://dx.doi.org/10.1093/nar/gkae642 | DOI Listing |
JMIR Form Res
December 2024
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States.
Background: Web-based information and social support are commonly used in rare disease communities where geographic dispersion and limited provider expertise complicate in-person support. We examined web-based resource use among caregivers of individuals with telomere biology disorders (TBDs), which are rare genetic conditions with long diagnostic odysseys and uncertain prognoses including multiorgan system cancer risk.
Objective: This study explored internet-based information-seeking and social support practices and perspectives of patients with TBDs and their caregivers.
Mol Biol Rep
October 2024
Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana, 124001, India.
Three-stranded DNA: RNA hybrids known as R-loops form when the non-template DNA strand is displaced and the mRNA transcript anneals to its template strand. Although R-loop formation controls DNA damage response, mitochondrial and genomic transcription, and physiological R-loop formation, imbalanced formation of R-loop can jeopardize a cell's genomic integrity. Transcription regulation and immunoglobulin class switch recombination are two further specialized functions of genomic R-loops.
View Article and Find Full Text PDFInt J Mol Sci
September 2024
Discovery, InsideOutBio, 42 8th Street, Unit 3412, Charlestown, MA 02129, USA.
Am J Hum Genet
November 2024
Whitehead Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:
Eur Rev Aging Phys Act
October 2024
Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, People's Republic of China.
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