title: TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions.
abstract: Repressor/activator protein 1 (RAP1) is a highly conserved telomere-interacting protein. Yeast Rap1 protects telomeres from non-homologous end joining (NHEJ), plays important roles in telomere length control and is involved in transcriptional gene regulation. However, a role for mammalian RAP1 in telomere end protection remains controversial. Here we present evidence that mammalian RAP1 is essential to protect telomere from homology directed repair (HDR) of telomeres. RAP1 cooperates with the basic domain of TRF2 (TRF2(B)) to repress PARP1 and SLX4 localization to telomeres. Without RAP1 and TRF2(B), PARP1 and SLX4 HR factors promote rapid telomere resection, resulting in catastrophic telomere loss and the generation of telomere-free chromosome fusions in both mouse and human cells. The RAP1 Myb domain is required to repress both telomere loss and formation of telomere-free fusions. Our results highlight the importance of the RAP1-TRF2 heterodimer in protecting telomeres from inappropriate processing by the HDR pathway.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06520, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rai
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 333, Haike Rd., Shanghai 201210, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 333, Haike Rd., Shanghai 201210, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06520, USA.|Department of Pathology, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 330 Cedar Street, New Haven, Connecticut 06520, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
mesh_terms: D000818:Animals; D002460:Cell Line; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D021381:Protein Transport; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D016615:Telomere / Q000502:physiology; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C556015:PARPBP protein, human; D011994:Recombinant Proteins; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C440809:TERF2IP protein, human; C548558:TERF2IP protein, mouse; C534796:TRF2 protein, mouse; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2