title: TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres.
abstract: The regulation of 5' end resection at DSBs and telomeres prevents genome instability. DSB resection is positively and negatively regulated by ATM signaling through CtIP/MRN and 53BP1-bound Rif1, respectively. Similarly, telomeres lacking TRF2 undergo ATM-controlled CtIP-dependent hyper-resection when the repression by 53BP1/Rif1 is alleviated. However, telomere resection in the absence of 53BP1/Rif1 is more extensive upon complete removal of shelterin, indicating additional protection against resection by shelterin. Here we show that TPP1 and POT1a/b in shelterin block a resection pathway distinct from that repressed by TRF2. This second pathway is regulated by ATR signaling, involves Exo1 and BLM, and is inhibited by 53BP1/Rif1. Thus, mammalian cells have two distinct 5' end-resection pathways that are regulated by DNA damage signaling, in part through Rif1-mediated inhibition. The data show that telomeres are protected from hyper-resection through the repression of the ATM and ATR kinases by TRF2 and TPP1-bound POT1a/b, respectively.
authors.affiliation: Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kibe
authors.affiliation: Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: delange@rockefeller.edu.
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000626:Aminopeptidases; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; D057057:Serine Proteases; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D000071857:Tumor Suppressor p53-Binding Protein 1; C544060:Acd protein, mouse; C501070:RBBP8 protein, mouse; C492748:Rif1 protein, mouse; C498302:Trp53bp1 protein, mouse; C576897:Atr protein, mouse; C583623:Exo1 protein, mouse; C097151:Bloom syndrome protein
keywords: 53BP1; Rif1; resection; telomere