![]() During DNA replication, replication forks can be stalled by external and intrinsic obstacles, leading to processing of nascent DNA ends to enable replication restart. Maintaining efficient error-free replication of the genome is key to preventing genome instability. Genome instability is a leading factor contributing to cancer. Our observations uncover the pathway by which budding yeast Rif1 stabilises newly synthesised DNA, highlighting the crucial role Rif1 plays in maintaining genome stability from lower eukaryotes to humans. We find that nascent DNA protection depends on a cluster of Tel1/Mec1 consensus phosphorylation sites in the Rif1 protein sequence, indicating that the intra-S phase checkpoint acts to protect nascent DNA through Rif1 phosphorylation. Yeast Rif1 was previously identified as a target of phosphorylation by the Tel1/Mec1 checkpoint kinases, but the importance of this phosphorylation has been unclear. This functional role for Rif1 is conserved from yeast to human cells. In the absence of Rif1, removal of either Dna2 or Sgs1 prevents nascent DNA degradation, implying that Rif1 protects nascent DNA by targeting Protein Phosphatase 1 to oppose degradation by the Sgs1-Dna2 nuclease-helicase complex. ![]() ![]() Here we show that budding yeast Rif1 must interact with Protein Phosphatase 1 to protect nascent DNA. Genome Biol 20(1):58ĭurbin R, Eddy S, Krogh A, Mitchison G (1998) Biological sequence analysis: probabilistic models of proteins and nucleic acids.In budding yeast the Rif1 protein is important for protecting nascent DNA at blocked replication forks, but the mechanism has been unclear. Mitsuhashi S, Frith MC, Mizuguchi T, Miyatake S, Toyota T, Adachi H, Oma Y, Kino Y, Mitsuhashi H, Matsumoto N (2019) Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads. Hamada M, Ono Y, Asai K, Frith MC (2017) Training alignment parameters for arbitrary sequencers with LAST-TRAIN. Genome Med 12, 67 (2020).ĭe Coster W, De Rijk P, De Roeck A, De Pooter T, D’Hert S, Strazisar M, Sleegers K, Van Broeckhoven C (2019) Structural variants identified by Oxford Nanopore PromethION sequencing of the human genome. Nat Genet 51(8):1215–1221Ī pipeline for complete characterization of complex germline rearrangements from long DNA reads. Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K Koike H, Hashiguchi A, Takashima H, Sugiyama H, et al (2019) Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, Almansour MA, Kikuchi JK, Taira M, Mitsui J, et al (2019) Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Yeetong P, Pongpanich M, Srichomthong C, Assawapitaksakul A, Shotelersuk V, Tantirukdham N, Chunharas C, Suphapeetiporn K, Shotelersuk V (2019) TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4. Nat Commun 10(1):1–14Ĭorbett MA, Kroes T, Veneziano L, Bennett MF, Florian R, Schneider AL, Coppola A, Licchetta L, Franceschetti S, Suppa A, et al (2019) Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun 8(1):1–13įlorian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, vanRootselaar A-F, Buratti J, Kühnel T, Schröder C, et al (2019) Unstable TTTTA/TTTCA expansions in MARCH6 are associated with familial adult myoclonic epilepsy type 3. Stancu MC, Van Roosmalen MJ, Renkens I, Nieboer MM, Middelkamp S, De Ligt J, Pregno G, Giachino D, Mandrile G, Valle-Inclan JE, et al (2017) Mapping and phasing of structural variation in patient genomes using nanopore sequencing. Sakamoto Y, Sereewattanawoot S, Suzuki A (2019) A new era of long-read sequencing for cancer genomics. ![]() ![]() Mongan AE, Tuda JSB, Runtuwene LR (2019) Portable sequencer in the fight against infectious disease. Mitsuhashi S, Matsumoto N (2019) Long-read sequencing for rare human genetic diseases. ![]()
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