Skip to main content

Rif1-Dependent Regulation of Genome Replication in Mammals

  • Chapter
  • First Online:
DNA Replication

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1042))

Abstract

Eukaryotic genomes are replicated starting from multiple origins of replication. Their usage is tightly regulated, and not all the potential origins are activated during a single cell cycle. In addition, the ones that are activated are activated in a sequential order. Why don’t origins of replication normally all fire together? Is this important? And if so, why? Would any order of firing do, or does the specific sequence matter? How is this process regulated? These questions concern all eukaryotes but have proven extremely hard to address because replication timing is a process intricately connected with multiple aspects of nuclear function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  • Alver RC, Chadha GS, Gillespie PJ, Blow JJ (2017) Reversal of DDK-mediated MCM phosphorylation by Rif1-PP1 regulates replication initiation and replisome stability independently of ATR/Chk1. Cell Rep 18:2508–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrulis ED, Neiman AM, Zappulla DC, Sternglanz R (1998) Perinuclear localization of chromatin facilitates transcriptional silencing. Nature 394:592–595

    Article  CAS  PubMed  Google Scholar 

  • Arnoult N, Schluth-Bolard C, Letessier A, Drascovic I, Bouarich-Bourimi R, Campisi J, Kim SH, Boussouar A, Ottaviani A, Magdinier F et al (2010) Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization. PLoS Genet 6:e1000920

    Article  PubMed  PubMed Central  Google Scholar 

  • Bianchi A, Shore D (2007) Early replication of short telomeres in budding yeast. Cell 128:1051–1062

    Article  CAS  PubMed  Google Scholar 

  • Brazda V, Laister RC, Jagelska EB, Arrowsmith C (2011) Cruciform structures are a common DNA feature important for regulating biological processes. BMC Mol Biol 12:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buonomo SB, Wu Y, Ferguson D, de Lange T (2009) Mammalian Rif1 contributes to replication stress survival and homology-directed repair. J Cell Biol 187:385–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, Sartori AA, Adams IR, Batista FD, Boulton SJ (2013) RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell 49:858–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conrad MN, Wright JH, Wolf AJ, Zakian VA (1990) RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability. Cell 63:739–750

    Article  CAS  PubMed  Google Scholar 

  • Cornacchia D, Dileep V, Quivy JP, Foti R, Tili F, Santarella-Mellwig R, Antony C, Almouzni G, Gilbert DM, Buonomo SB (2012) Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J 31:3678–3690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daley JM, Sung P (2013) RIF1 in DNA break repair pathway choice. Mol Cell 49:840–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dave A, Cooley C, Garg M, Bianchi A (2014) Protein phosphatase 1 recruitment by Rif1 regulates DNA replication origin firing by counteracting DDK activity. Cell Rep 7:53–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diede SJ, Gottschling DE (1999) Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases alpha and delta. Cell 99:723–733

    Article  CAS  PubMed  Google Scholar 

  • Dileep V, Ay F, Sima J, Vera DL, Noble WS, Gilbert DM (2015) Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program. Genome Res 25(8):1104–1113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dimitrova DS, Gilbert DM (1999) The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell 4:983–993

    Article  CAS  PubMed  Google Scholar 

  • Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkac J, Cook MA, Rosebrock AP, Munro M, Canny MD et al (2013) A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 49:872–883

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Fong KW, Wang J, Wang W, Chen J (2013) RIF1 counteracts BRCA1-mediated end resection during DNA repair. J Biol Chem 288:11135–11143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finlan LE, Sproul D, Thomson I, Boyle S, Kerr E, Perry P, Ylstra B, Chubb JR, Bickmore WA (2008) Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet 4:e1000039

    Article  PubMed  PubMed Central  Google Scholar 

  • Foti R, Gnan S, Cornacchia D, Dileep V, Bulut-Karslioglu A, Diehl S, Buness A, Klein FA, Huber W, Johnstone E et al (2016) Nuclear architecture organized by Rif1 underpins the replication-timing program. Mol Cell 61:260–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu YV, Yardimci H, Long DT, Ho TV, Guainazzi A, Bermudez VP, Hurwitz J, van Oijen A, Scharer OD, Walter JC (2011) Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146:931–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallardo F, Laterreur N, Cusanelli E, Ouenzar F, Querido E, Wellinger RJ, Chartrand P (2011) Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres. Mol Cell 44:819–827

    Article  CAS  PubMed  Google Scholar 

  • Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O et al (2011) A protein complex network of Drosophila melanogaster. Cell 147:690–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardy CF, Sussel L, Shore D (1992) A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. Genes Dev 6:801–814

    Article  CAS  PubMed  Google Scholar 

  • Hayano M, Kanoh Y, Matsumoto S, Renard-Guillet C, Shirahige K, Masai H (2012) Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes Dev 26:137–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiraga S, Alvino GM, Chang F, Lian HY, Sridhar A, Kubota T, Brewer BJ, Weinreich M, Raghuraman MK, Donaldson AD (2014) Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes Dev 28:372–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiraga SI, Ly T, Garzon J, Horejsi Z, Ohkubo YN, Endo A, Obuse C, Boulton SJ, Lamond AI, Donaldson AD (2017) Human RIF1 and protein phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation. EMBO Rep 18:403–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiratani I, Ryba T, Itoh M, Yokochi T, Schwaiger M, Chang CW, Lyou Y, Townes TM, Schubeler D, Gilbert DM (2008) Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 6:e245

    Article  PubMed  PubMed Central  Google Scholar 

  • Hiratani I, Ryba T, Itoh M, Rathjen J, Kulik M, Papp B, Fussner E, Bazett-Jones DP, Plath K, Dalton S et al (2010) Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res 20:155–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hultdin M, Gronlund E, Norrback KF, Just T, Taneja K, Roos G (2001) Replication timing of human telomeric DNA and other repetitive sequences analyzed by fluorescence in situ hybridization and flow cytometry. Exp Cell Res 271:223–229

    Article  CAS  PubMed  Google Scholar 

  • Kanoh Y, Matsumoto S, Fukatsu R, Kakusho N, Kono N, Renard-Guillet C, Masuda K, Iida K, Nagasawa K, Shirahige K et al (2015) Rif1 binds to G quadruplexes and suppresses replication over long distances. Nat Struct Mol Biol 22:889–897

    Article  CAS  PubMed  Google Scholar 

  • Knott SR, Peace JM, Ostrow AZ, Gan Y, Rex AE, Viggiani CJ, Tavare S, Aparicio OM (2012) Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae. Cell 148:99–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levy DL, Blackburn EH (2004) Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length. Mol Cell Biol 24:10857–10867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian HY, Robertson ED, Hiraga S, Alvino GM, Collingwood D, McCune HJ, Sridhar A, Brewer BJ, Raghuraman MK, Donaldson AD (2011) The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation. Mol Biol Cell 22:1753–1765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science (New York, NY) 326:289–293

    Article  CAS  Google Scholar 

  • Lustig AJ, Kurtz S, Shore D (1990) Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length. Science (New York, NY) 250:549–553

    Article  CAS  Google Scholar 

  • Mantiero D, Mackenzie A, Donaldson A, Zegerman P (2011) Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J 30:4805–4814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martina M, Bonetti D, Villa M, Lucchini G, Longhese MP (2014) Saccharomyces cerevisiae Rif1 cooperates with MRX-Sae2 in promoting DNA-end resection. EMBO Rep 15:695–704

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mattarocci S, Shyian M, Lemmens L, Damay P, Altintas DM, Shi T, Bartholomew CR, Thoma NH, Hardy CF, Shore D (2014) Rif1 controls DNA replication timing in yeast through the PP1 phosphatase Glc7. Cell Rep 7:62–69

    Article  CAS  PubMed  Google Scholar 

  • Mattarocci S, Hafner L, Lezaja A, Shyian M, Shore D (2016) Rif1: a conserved regulator of DNA replication and repair hijacked by telomeres in yeasts. Front Genet 7(e1002024):45

    PubMed  PubMed Central  Google Scholar 

  • Mattout A, Pike BL, Towbin BD, Bank EM, Gonzalez-Sandoval A, Stadler MB, Meister P, Gruenbaum Y, Gasser SM (2011) An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity. Curr Biol 21:1603–1614

    Article  CAS  PubMed  Google Scholar 

  • Moorhead GB, Trinkle-Mulcahy L, Nimick M, De Wever V, Campbell DG, Gourlay R, Lam YW, Lamond AI (2008) Displacement affinity chromatography of protein phosphatase one (PP1) complexes. BMC Biochem 9:28

    Article  PubMed  PubMed Central  Google Scholar 

  • Patel PK, Arcangioli B, Baker SP, Bensimon A, Rhind N (2006) DNA replication origins fire stochastically in fission yeast. Mol Biol Cell 17:308–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peace JM, Ter-Zakarian A, Aparicio OM (2014) Rif1 regulates initiation timing of late replication origins throughout the S. cerevisiae genome. PLoS One 9:e98501

    Article  PubMed  PubMed Central  Google Scholar 

  • Peric-Hupkes D, Meuleman W, Pagie L, Bruggeman SW, Solovei I, Brugman W, Graf S, Flicek P, Kerkhoven RM, van Lohuizen M et al (2010) Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell 38:603–613

    Article  CAS  PubMed  Google Scholar 

  • Pope BD, Ryba T, Dileep V, Yue F, Wu W, Denas O, Vera DL, Wang Y, Hansen RS, Canfield TK et al (2014) Topologically associating domains are stable units of replication-timing regulation. Nature 515:402–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raghuraman MK, Brewer BJ, Fangman WL (1997) Cell cycle-dependent establishment of a late replication program. Science (New York, NY) 276:806–809

    Article  CAS  Google Scholar 

  • Reddy KL, Zullo JM, Bertolino E, Singh H (2008) Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452:243–247

    Article  CAS  PubMed  Google Scholar 

  • Rivera-Mulia JC, Gilbert DM (2016) Replication timing and transcriptional control: beyond cause and effect-part III. Curr Opin Cell Biol 40:168–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rivera-Mulia JC, Buckley Q, Sasaki T, Zimmerman J, Didier RA, Nazor K, Loring JF, Lian Z, Weissman S, Robins AJ et al (2015) Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. Genome Res 25:1091–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roux KJ, Kim DI, Raida M, Burke B (2012) A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. J Cell Biol 196:801–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryba T, Hiratani I, Lu J, Itoh M, Kulik M, Zhang J, Schulz TC, Robins AJ, Dalton S, Gilbert DM (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res 20:761–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos M, Rebelo S, Van Kleeff PJ, Kim CE, Dauer WT, Fardilha M, da Cruz ESOA, da Cruz ESEF (2013) The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. PLoS One 8:e76788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sazer S, Lynch M, Needleman D (2014) Deciphering the evolutionary history of open and closed mitosis. Curr Biol 24:R1099–R1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi T, Bunker RD, Mattarocci S, Ribeyre C, Faty M, Gut H, Scrima A, Rass U, Rubin SM, Shore D et al (2013) Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. Cell 153:1340–1353

    Article  CAS  PubMed  Google Scholar 

  • Shimi T, Butin-Israeli V, Adam SA, Goldman RD (2010) Nuclear lamins in cell regulation and disease. Cold Spring Harb Symp Quant Biol 75:525–531

    Article  CAS  PubMed  Google Scholar 

  • Silverman J, Takai H, Buonomo SB, Eisenhaber F, de Lange T (2004) Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev 18:2108–2119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sreesankar E, Senthilkumar R, Bharathi V, Mishra RK, Mishra K (2012) Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes. BMC Genomics 13:255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sreesankar E, Bharathi V, Mishra RK, Mishra K (2015) Drosophila Rif1 is an essential gene and controls late developmental events by direct interaction with PP1-87B. Sci Rep 5:10679

    Article  PubMed  PubMed Central  Google Scholar 

  • Steen RL, Martins SB, Tasken K, Collas P (2000) Recruitment of protein phosphatase 1 to the nuclear envelope by A-kinase anchoring protein AKAP149 is a prerequisite for nuclear lamina assembly. J Cell Biol 150:1251–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukackaite R, Jensen MR, Mas PJ, Blackledge M, Buonomo SB, Hart DJ (2014) Structural and biophysical characterization of murine Rif1 C terminus reveals high specificity for DNA cruciform structures. J Biol Chem 289:13903–13911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukackaite R, Cornacchia D, Jensen MR, Mas PJ, Blackledge M, Enervald E, Duan G, Auchynnikava T, Kohn M, Hart DJ et al (2017) Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1). Sci Rep 7:2119

    Article  PubMed  PubMed Central  Google Scholar 

  • Takebayashi S, Dileep V, Ryba T, Dennis JH, Gilbert DM (2012) Chromatin-interaction compartment switch at developmentally regulated chromosomal domains reveals an unusual principle of chromatin folding. Proc Natl Acad Sci U S A 109:12574–12579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka S, Nakato R, Katou Y, Shirahige K, Araki H (2011) Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr Biol 21:2055–2063

    Article  CAS  PubMed  Google Scholar 

  • Teixeira MT, Arneric M, Sperisen P, Lingner J (2004) Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117:323–335

    Article  CAS  PubMed  Google Scholar 

  • Trinkle-Mulcahy L, Andersen J, Lam YW, Moorhead G, Mann M, Lamond AI (2006) Repo-Man recruits PP1 gamma to chromatin and is essential for cell viability. J Cell Biol 172:679–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang et al (2009) Human RIF1 encodes an anti-apoptotic factor required for DNA repair. Carcinogenesis 8:1314–1319

    Google Scholar 

  • Williams RR, Azuara V, Perry P, Sauer S, Dvorkina M, Jorgensen H, Roix J, McQueen P, Misteli T, Merkenschlager M et al (2006) Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J Cell Sci 119:132–140

    Article  CAS  PubMed  Google Scholar 

  • Wright WE, Tesmer VM, Liao ML, Shay JW (1999) Normal human telomeres are not late replicating. Exp Cell Res 251:492–499

    Article  CAS  PubMed  Google Scholar 

  • Wu PY, Nurse P (2009) Establishing the program of origin firing during S phase in fission yeast. Cell 136:852–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L, Blackburn EH (2004) Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules. J Cell Biol 167:819–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu D, Muniandy P, Leo E, Yin J, Thangavel S, Shen X, Ii M, Agama K, Guo R, Fox D 3rd et al (2010) Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. EMBO J 29:3140–3155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yaffe E, Farkash-Amar S, Polten A, Yakhini Z, Tanay A, Simon I (2010) Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet 6:e1001011

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamazaki S, Ishii A, Kanoh Y, Oda M, Nishito Y, Masai H (2012) Rif1 regulates the replication timing domains on the human genome. EMBO J 31:3667–3677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Ermakova OV, Riblet R, Birshtein BK, Schildkraut CL (2002) Replication and subnuclear location dynamics of the immunoglobulin heavy-chain locus in B-lineage cells. Mol Cell Biol 22:4876–4889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zou Y, Gryaznov SM, Shay JW, Wright WE, Cornforth MN (2004) Asynchronous replication timing of telomeres at opposite arms of mammalian chromosomes. Proc Natl Acad Sci U S A 101:12928–12933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zullo JM, Demarco IA, Pique-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL et al (2012) DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149:1474–1487

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

I would like to thank past and present members of the Buonomo group for their work that is the base of this review and the invaluable scientific contribution. I am also grateful to Svetlana Makovets and Elizabeth Bayne for critical reading of the manuscript and helpful suggestions. I apologize for the references omitted due to general nature of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sara B. C. Buonomo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Buonomo, S.B.C. (2017). Rif1-Dependent Regulation of Genome Replication in Mammals. In: Masai, H., Foiani, M. (eds) DNA Replication. Advances in Experimental Medicine and Biology, vol 1042. Springer, Singapore. https://doi.org/10.1007/978-981-10-6955-0_12

Download citation

Publish with us

Policies and ethics