Replication licensing and cancer — a fatal entanglement?

Correct regulation of the replication licensing system ensures that chromosomal DNA is precisely duplicated in each cell division cycle. Licensing proteins are inappropriately expressed at an early stage of tumorigenesis in a wide variety of cancers. Here we discuss evidence that misregulation of replication licensing is a consequence of oncogene-induced cell proliferation. This misregulation can cause either under- or over-replication of chromosomal DNA, and could explain the genetic instability commonly seen in cancer cells.

[1]  Anindya Dutta,et al.  An ATR- and BRCA1-Mediated Fanconi Anemia Pathway Is Required for Activating the G2/M Checkpoint and DNA Damage Repair upon Rereplication , 2006, Molecular and Cellular Biology.

[2]  Anindya Dutta,et al.  A p53-dependent checkpoint pathway prevents rereplication. , 2003, Molecular cell.

[3]  A. Carr,et al.  Checkpoint responses to replication fork barriers. , 2005, Biochimie.

[4]  Bruce Stillman,et al.  Deregulation of cyclin E in human cells interferes with prereplication complex assembly , 2004, The Journal of cell biology.

[5]  C. Newlon,et al.  Regulation of DNA replication fork progression through damaged DNA by the Mec 1 / Rad 53 checkpoint , 2022 .

[6]  S. Forsburg,et al.  Reduced dosage of a single fission yeast MCM protein causes genetic instability and S phase delay. , 1999, Journal of cell science.

[7]  P. Nurse,et al.  Maintenance of replication forks and the S-phase checkpoint by Cdc18p and Orp1p , 2002, Nature Cell Biology.

[8]  B. Tye,et al.  A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice , 2007, Nature Genetics.

[9]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[10]  E. Kipreos,et al.  C. elegans CUL-4 Prevents Rereplication by Promoting the Nuclear Export of CDC-6 via a CKI-1-Dependent Pathway , 2007, Current Biology.

[11]  M. Kirschner,et al.  Geminin, an Inhibitor of DNA Replication, Is Degraded during Mitosis , 1998, Cell.

[12]  T. Pandita,et al.  Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53 , 2005, Oncogene.

[13]  J. Walter,et al.  Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. , 2007, Genes & development.

[14]  M. DePamphilis,et al.  Regulating the licensing of DNA replication origins in metazoa. , 2006, Current opinion in cell biology.

[15]  Wei Jiang,et al.  The role of pre‐replicative complex (pre‐RC) components in oncogenesis , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  M. Botchan,et al.  Isolation of the Cdc45/Mcm2–7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase , 2006, Proceedings of the National Academy of Sciences.

[17]  R. Knippers,et al.  Interactions of human nuclear proteins P1Mcm3 and P1Cdc46. , 1995, European journal of biochemistry.

[18]  J. Pines,et al.  Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1 , 2003, The EMBO journal.

[19]  C. McCall,et al.  Targeted ubiquitination of CDT1 by the DDB1–CUL4A–ROC1 ligase in response to DNA damage , 2004, Nature Cell Biology.

[20]  J. Blow,et al.  Reconstitution of licensed replication origins on Xenopus sperm nuclei using purified proteins , 2001, BMC Biochemistry.

[21]  A. Rustgi,et al.  Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. , 2007, Genes & development.

[22]  R. Abraham,et al.  Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling , 2004, The EMBO journal.

[23]  L. Cooley,et al.  Control of DNA Replication and Chromosome Ploidy by Geminin and Cyclin A , 2002, Molecular and Cellular Biology.

[24]  Joachim J Li,et al.  Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage. , 2004, Molecular biology of the cell.

[25]  M. Lei.  The MCM complex: its role in DNA replication and implications for cancer therapy. , 2005, Current cancer drug targets.

[26]  K. Stoeber,et al.  Cell cycle markers in clinical oncology. , 2007, Current opinion in cell biology.

[27]  F. d’Adda di Fagagna,et al.  Breaking news: high-speed race ends in arrest--how oncogenes induce senescence. , 2007, Trends in cell biology.

[28]  A. Amsterdam,et al.  DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. , 2006, Genes & development.

[29]  J. Julian Blow,et al.  Preventing re-replication of chromosomal DNA , 2005, Nature Reviews Molecular Cell Biology.

[30]  Zoi Lygerou,et al.  The Human Licensing Factor for DNA Replication Cdt1 Accumulates in G1 and Is Destabilized after Initiation of S-phase* , 2001, The Journal of Biological Chemistry.

[31]  J. Blow,et al.  Cell Cycle Regulation of the Replication Licensing System: Involvement of a Cdk-dependent Inhibitor , 1997, The Journal of cell biology.

[32]  R. Laskey,et al.  MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells , 1995, Nature.

[33]  J. Hamlin,et al.  Cdc6 Chromatin Affinity Is Unaffected by Serine-54 Phosphorylation, S-Phase Progression, and Overexpression of Cyclin A , 2004, Molecular and Cellular Biology.

[34]  J. Blow,et al.  Non-proteolytic inactivation of geminin requires CDK-dependent ubiquitination , 2004, Nature Cell Biology.

[35]  E. Kipreos,et al.  CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing , 2003, Nature.

[36]  A. Gartner,et al.  Excess Mcm2–7 license dormant origins of replication that can be used under conditions of replicative stress , 2006, The Journal of cell biology.

[37]  James M. Roberts,et al.  A mouse model for cyclin E-dependent genetic instability and tumorigenesis. , 2005, Cancer cell.

[38]  M. Méchali,et al.  Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin , 2001, Nature Cell Biology.

[39]  J. Walter,et al.  Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. , 2005, Genes & development.

[40]  J. Blow,et al.  Deregulated Replication Licensing Causes DNA Fragmentation Consistent with Head-to-Tail Fork Collision , 2006, Molecular cell.

[41]  A. Amsterdam,et al.  DTL / CDT 2 is essential for both CDT 1 regulation and the early G 2 / M checkpoint , 2006 .

[42]  D. Lane,et al.  Cell type-specific responses of human cells to inhibition of replication licensing , 2002, Oncogene.

[43]  Zoi Lygerou,et al.  The Cdt1 protein is required to license DNA for replication in fission yeast , 2000, Nature.

[44]  J. Blow,et al.  Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re‐replication in Xenopus , 2005, The EMBO journal.

[45]  Y. Tatsumi,et al.  Identification of novel human Cdt1-binding proteins by a proteomics approach: proteolytic regulation by APC/CCdh1. , 2007, Molecular biology of the cell.

[46]  Etienne Schwob,et al.  The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1). , 2002, Molecular cell.

[47]  D. Cortez,et al.  DDB1 Maintains Genome Integrity through Regulation of Cdt1 , 2006, Molecular and Cellular Biology.

[48]  S. Reed,et al.  Deregulated cyclin E induces chromosome instability , 1999, Nature.

[49]  Anindya Dutta,et al.  PCNA Is a Cofactor for Cdt1 Degradation by CUL4/DDB1-mediated N-terminal Ubiquitination* , 2006, Journal of Biological Chemistry.

[50]  J. H. Taylor.  Increase in DNA replication sites in cells held at the beginning of S phase , 1977, Chromosoma.

[51]  J. Bartek,et al.  Loss of Geminin induces rereplication in the presence of functional p53 , 2004, The Journal of cell biology.

[52]  P. Nurse,et al.  Cdc18 enforces long-term maintenance of the S phase checkpoint by anchoring the Rad3-Rad26 complex to chromatin. , 2007, Molecular cell.

[53]  P. Klatt,et al.  Oncogenic activity of Cdc6 through repression of the INK4/ARF locus , 2006, Nature.

[54]  Anindya Dutta,et al.  APC/C – the master controller of origin licensing? , 2007, Cell Division.

[55]  Xiaohua Wu,et al.  The SCFSkp2 Ubiquitin Ligase Complex Interacts with the Human Replication Licensing Factor Cdt1 and Regulates Cdt1 Degradation* , 2003, Journal of Biological Chemistry.

[56]  J. Méndez,et al.  CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. , 2008, Carcinogenesis.

[57]  K. Nakayama,et al.  Two E3 ubiquitin ligases, SCF‐Skp2 and DDB1‐Cul4, target human Cdt1 for proteolysis , 2006, The EMBO journal.

[58]  E. Boye,et al.  DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1 , 2006, EMBO reports.

[59]  H. Nojima,et al.  Identification of the yeast MCM3-related protein as a component of xenopus DNA replication licensing factor , 1995, Cell.

[60]  J. Blow,et al.  The role of Cdc6 in ensuring complete genome licensing and S phase checkpoint activation , 2004, The Journal of cell biology.

[61]  T. McGarry,et al.  The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis. , 2001, Genes & development.

[62]  J Julian Blow,et al.  The chromosome cycle: coordinating replication and segregation , 2005, EMBO reports.

[63]  J. Blow,et al.  Geminin Becomes Activated as an Inhibitor of Cdt1/RLF-B Following Nuclear Import , 2002, Current Biology.

[64]  Dimitris Kletsas,et al.  Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. , 2007, Cancer research.

[65]  Jamie K Teer,et al.  Acute Reduction of an Origin Recognition Complex (ORC) Subunit in Human Cells Reveals a Requirement of ORC for Cdk2 Activation* , 2005, Journal of Biological Chemistry.

[66]  E. Schwob,et al.  Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication , 2008, Proceedings of the National Academy of Sciences.

[67]  Michael A. Gonzalez,et al.  Control of DNA replication and its potential clinical exploitation , 2005, Nature Reviews Cancer.

[68]  Y. Xiong,et al.  An Evolutionarily Conserved Function of Proliferating Cell Nuclear Antigen for Cdt1 Degradation by the Cul4-Ddb1 Ubiquitin Ligase in Response to DNA Damage* , 2006, Journal of Biological Chemistry.

[69]  J. Swedlow,et al.  ELYS/MEL-28 Chromatin Association Coordinates Nuclear Pore Complex Assembly and Replication Licensing , 2007, Current Biology.

[70]  J. Diffley,et al.  Is the MCM2-7 complex the eukaryotic DNA replication fork helicase? , 2001, Current opinion in genetics & development.

[71]  T. Prokhorova,et al.  MCM 2 – 7 Complexes Bind Chromatin in a Distributed Pattern Surrounding the Origin Recognition Complex in Xenopus Egg Extracts , 2002 .

[72]  A. Montagnoli,et al.  Cdc7 Inhibition Reveals a p53-Dependent Replication Checkpoint That Is Defective in Cancer Cells , 2004, Cancer Research.

[73]  Tony Hunter,et al.  Minichromosome Maintenance Proteins Interact with Checkpoint and Recombination Proteins To Promote S-Phase Genome Stability , 2008, Molecular and Cellular Biology.

[74]  J. Walter,et al.  PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication , 2006, Nature Cell Biology.

[75]  Anindya Dutta,et al.  Mechanisms to control rereplication and implications for cancer. , 2007, Current opinion in cell biology.

[76]  Z. Tu,et al.  Inhibiting the expression of DNA replication-initiation proteins induces apoptosis in human cancer cells. , 2003, Cancer research.

[77]  N. Lehman,et al.  Loss of Emi1-Dependent Anaphase-Promoting Complex/Cyclosome Inhibition Deregulates E2F Target Expression and Elicits DNA Damage-Induced Senescence , 2007, Molecular and Cellular Biology.

[78]  Anindya Dutta,et al.  The APC/C inhibitor, Emi1, is essential for prevention of rereplication. , 2007, Genes & development.

[79]  J. Diffley,et al.  Nucleotide-dependent prereplicative complex assembly by Cdc6p, a homolog of eukaryotic and prokaryotic clamp-loaders. , 1998, Molecular cell.

[80]  D. Takeda,et al.  Degradation of Cdt1 during S Phase Is Skp2-independent and Is Required for Efficient Progression of Mammalian Cells through S Phase* , 2005, Journal of Biological Chemistry.

[81]  J. Parvin,et al.  Human CDC6/Cdc18 Associates with Orc1 and Cyclin-cdk and Is Selectively Eliminated from the Nucleus at the Onset of S Phase , 1998, Molecular and Cellular Biology.

[82]  B. Calvi,et al.  Drosophila double-parked is sufficient to induce re-replication during development and is regulated by cyclin E/CDK2 , 2004, Development.

[83]  Seiji Tanaka,et al.  Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation. , 2002, Genes & development.

[84]  A. Coxon,et al.  Fission yeast cdc21+ belongs to a family of proteins involved in an early step of chromosome replication. , 1992, Nucleic acids research.

[85]  Xin Quan Ge,et al.  Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. , 2007, Genes & development.

[86]  J. Pines,et al.  Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C , 2007, The Journal of cell biology.

[87]  Anindya Dutta,et al.  Rereplication by Depletion of Geminin Is Seen Regardless of p53 Status and Activates a G2/M Checkpoint , 2004, Molecular and Cellular Biology.

[88]  J. Blow,et al.  Replication licensing — Origin licensing: defining the proliferative state? , 2002 .

[89]  N. Lehman,et al.  Overexpression of the Anaphase Promoting Complex/Cyclosome Inhibitor Emi1 Leads to Tetraploidy and Genomic Instability of p53-Deficient Cells , 2006, Cell cycle.

[90]  Amy Freeland,et al.  Reduced Mcm2 Expression Results in Severe Stem/Progenitor Cell Deficiency and Cancer , 2007, Stem cells.

[91]  D. Gilbert.  Replication origin plasticity, Taylor-made: inhibition vs recruitment of origins under conditions of replication stress , 2007, Chromosoma.

[92]  D. Fremont,et al.  Oncogenic potential of the DNA replication licensing protein CDT1 , 2002, Oncogene.

[93]  H. Okayama,et al.  Cdc6 Determines Utilization of p21WAF1/CIP1-dependent Damage Checkpoint in S Phase Cells* , 2008, Journal of Biological Chemistry.

[94]  M. Lei,et al.  Physical interactions among Mcm proteins and effects of Mcm dosage on DNA replication in Saccharomyces cerevisiae , 1996, Molecular and cellular biology.

[95]  Xiaohua Wu,et al.  Cyclin-dependent Kinases Phosphorylate Human Cdt1 and Induce Its Degradation* , 2004, Journal of Biological Chemistry.

[96]  J. Peters,et al.  Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. , 2000, Genes & development.

[97]  Anindya Dutta,et al.  Proliferating Human Cells Hypomorphic for Origin Recognition Complex 2 and Pre-replicative Complex Formation Have a Defect in p53 Activation and Cdk2 Kinase Activation* , 2006, Journal of Biological Chemistry.

[98]  J A Wohlschlegel,et al.  Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. , 2000, Science.

[99]  G. Williams,et al.  DNA replication licensing and human cell proliferation. , 2001, Journal of cell science.

[100]  T. Prokhorova,et al.  MCM2–7 Complexes Bind Chromatin in a Distributed Pattern Surrounding the Origin Recognition Complex inXenopus Egg Extracts* , 2002, The Journal of Biological Chemistry.

[101]  C. H. Ockey,et al.  The comparative effects of short-term DNA Inhibition on replicon synthesis in mammalian cells. , 1976, Experimental cell research.

[102]  G. Williams,et al.  Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[103]  F. Grummt,et al.  Mouse pre-replicative complex proteins colocalise and interact with the centrosome. , 2007, European journal of cell biology.

[104]  Aaron Bensimon,et al.  Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication , 2006, Nature.

[105]  J. Chen,et al.  A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. , 2006, Molecular cell.

[106]  J. Blow,et al.  Replication licensing--defining the proliferative state? , 2002, Trends in cell biology.

[107]  S. Ficarro,et al.  Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells. , 2006, Molecular biology of the cell.

[108]  J. Blow,et al.  Second in the Cycles Review Series , 2005 .

[109]  S. Elledge,et al.  Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[110]  James P. J. Chong,et al.  Purification of an MCM-containing complex as a component of the DNA replication licensing system , 1995, Nature.

[111]  J. Diffley,et al.  Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint , 2001, Nature.

[112]  H. Nishitani,et al.  DNA replication licensing. , 2004, Frontiers in bioscience : a journal and virtual library.

[113]  Jiri Bartek,et al.  Phosphorylation of mammalian CDC6 by Cyclin A/CDK2 regulates its subcellular localization , 1999, The EMBO journal.

[114]  Aaron Bensimon,et al.  Dynamics of DNA Replication in Mammalian Somatic Cells Nucleotide Pool Modulates Origin Choice and Interorigin Spacing , 2003, Cell.

[115]  P. Nurse,et al.  Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. , 2004, European journal of biochemistry.

[116]  Y. Tatsumi,et al.  Cdt1 Phosphorylation by Cyclin A-dependent Kinases Negatively Regulates Its Function without Affecting Geminin Binding* , 2004, Journal of Biological Chemistry.