Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis

被引：59

作者：

Bellelli, Roberto ^{[1
]}

Borel, Valerie ^{[1
]}

Logan, Clare ^{[2
]}

Svendsen, Jennifer ^{[1
]}

Cox, Danielle E. ^{[1
]}

Nye, Emma ^{[1
]}

Metcalfe, Kay ^{[3
]}

O'Connell, Susan M. ^{[4
]}

Stamp, Gordon ^{[1
]}

Flynn, Helen R. ^{[1
]}

Snijders, Ambrosius P. ^{[1
]}

Lassailly, Francois ^{[1
]}

Jackson, Andrew ^{[2
]}

Boulton, Simon J. ^{[1
]}

机构：

[1] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England

[2] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland

[3] St Marys Hosp, Dept Genet Med, Oxford Rd, Manchester M13 OJH, Lancs, England

[4] Cork Univ Hosp, Dept Paediat, Cork T12 DC4A, Ireland

来源：

MOLECULAR CELL | 2018年 / 70卷 / 04期

基金：

英国惠康基金; 欧洲研究理事会; 英国医学研究理事会;

关键词：

DNA-POLYMERASE-EPSILON; MEIER-GORLIN SYNDROME; ORIGIN RECOGNITION COMPLEX; KILLER-CELL DEFICIENCY; PRE-INITIATION COMPLEX; S-PHASE CHECKPOINT; SACCHAROMYCES-CEREVISIAE; GROWTH-RETARDATION; SHORT STATURE; HUMAN CANCER;

D O I：

10.1016/j.molcel.2018.04.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DNA polymerase epsilon (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Pol epsilon processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Pol epsilon complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4(-/-) mouse and POLE1 mutant human cells, Pol epsilon hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4(-/-) p53(+/-) mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention.

引用

页码：707 / +

页数：22

共 57 条

[1] Mismatch Repair-Independent Increase in Spontaneous Mutagenesis in Yeast Lacking Non-Essential Subunits of DNA Polymerase ε [J].

Aksenova, Anna ;

Volkov, Kirill ;

Maceluch, Jaroslaw ;

Pursell, Zachary F. ;

Rogozin, Igor B. ;

Kunkel, Thomas A. ;

Pavlov, Youri I. ;

Johansson, Erik .

PLOS GENETICS, 2010, 6 (11)

[2] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[3] CLONING DPB3, THE GENE ENCODING THE 3RD SUBUNIT OF DNA POLYMERASE-II OF SACCHAROMYCES-CEREVISIAE [J].

ARAKI, H ;

HAMATAKE, RK ;

MORRISON, A ;

JOHNSON, AL ;

JOHNSTON, LH ;

SUGINO, A .

NUCLEIC ACIDS RESEARCH, 1991, 19 (18) :4867-4872

[4] NCOA4 Transcriptional Coactivator Inhibits Activation of DNA Replication Origins [J].

Bellelli, Roberto ;

Castellone, Maria Domenica ;

Guida, Teresa ;

Limongello, Roberto ;

Dathan, Nina Alayne ;

Merolla, Francesco ;

Cirafici, Anna Maria ;

Affuso, Andrea ;

Masai, Hisao ;

Costanzo, Vincenzo ;

Grieco, Domenico ;

Fusco, Alfredo ;

Santoro, Massimo ;

Carlomagno, Francesca .

MOLECULAR CELL, 2014, 55 (01) :123-137

[5] Studies on Human DNA Polymerase ε and GINS Complex and Their Role in DNA Replication [J].

Bermudez, Vladimir P. ;

Farina, Andrea ;

Raghavan, Vineetha ;

Tappin, Inger ;

Hurwitz, Jerard .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (33) :28963-28977

[6] Mutations in the pre-replication complex cause Meier-Gorlin syndrome [J].

Bicknell, Louise S. ;

Bongers, Ernie M. H. F. ;

Leitch, Andrea ;

Brown, Stephen ;

Schoots, Jeroen ;

Harley, Margaret E. ;

Aftimos, Salim ;

Al-Aama, Jumana Y. ;

Bober, Michael ;

Brown, Paul A. J. ;

van Bokhoven, Hans ;

Dean, John ;

Edrees, Alaa Y. ;

Feingold, Murray ;

Fryer, Alan ;

Hoefsloot, Lies H. ;

Kau, Nikolaus ;

Knoers, Nine V. A. M. ;

MacKenzie, James ;

Opitz, John M. ;

Sarda, Pierre ;

Ross, Alison ;

Temple, I. Karen ;

Toutain, Annick ;

Wise, Carol A. ;

Wright, Michael ;

Jackson, Andrew P. .

NATURE GENETICS, 2011, 43 (04) :356-+

[7] Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome [J].

Bicknell, Louise S. ;

Walker, Sarah ;

Klingseisen, Anna ;

Stiff, Tom ;

Leitch, Andrea ;

Kerzendorfer, Claudia ;

Martin, Carol-Anne ;

Yeyati, Patricia ;

Al Sanna, Nouriya ;

Bober, Michael ;

Johnson, Diana ;

Wise, Carol ;

Jackson, Andrew P. ;

O'Driscoll, Mark ;

Jeggo, Penny A. .

NATURE GENETICS, 2011, 43 (04) :350-U103

[8] Comprehensive Analysis of Hypermutation in Human Cancer [J].

Campbell, Brittany B. ;

Light, Nicholas ;

Fabrizio, David ;

Zatzman, Matthew ;

Fuligni, Fabio ;

de Borja, Richard ;

Davidson, Scott ;

Edwards, Melissa ;

Elvin, Julia A. ;

Hodel, Karl P. ;

Zahurancik, Walter J. ;

Suo, Zucai ;

Lipman, Tatiana ;

Wimmer, Katharina ;

Kratz, Christian P. ;

Bowers, Daniel C. ;

Laetsch, Theodore W. ;

Dunn, Gavin P. ;

Johanns, Tanner M. ;

Grimmer, Matthew R. ;

Smirnov, Ivan V. ;

Larouche, Valerie ;

Samuel, David ;

Bronsema, Annika ;

Osborn, Michael ;

Stearns, Duncan ;

Raman, Pichai ;

Cole, Kristina A. ;

Storm, Phillip B. ;

Yalon, Michal ;

Opocher, Enrico ;

Mason, Gary ;

Thomas, Gregory A. ;

Sabel, Magnus ;

George, Ben ;

Ziegler, David S. ;

Lindhorst, Scott ;

Issai, Vanan Magimairajan ;

Constantini, Shlomi ;

Toledano, Helen ;

Elhasid, Ronit ;

Farah, Roula ;

Dvir, Rina ;

Dirks, Peter ;

Huang, Annie ;

Galati, Melissa A. ;

Chung, Jiil ;

Ramaswamy, Vijay ;

Irwin, Meredith S. ;

Aronson, Melyssa .

CELL, 2017, 171 (05) :1042-+

[9] Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency [J].

Cottineau, Julien ;

Kottemann, Molly C. ;

Lach, Francis P. ;

Kang, Young-Hoon ;

Vely, Frederic ;

Deenick, Elissa K. ;

Lazarov, Tomi ;

Gineau, Laure ;

Wang, Yi ;

Farina, Andrea ;

Chansel, Marie ;

Lorenzo, Lazaro ;

Piperoglou, Christelle ;

Ma, Cindy S. ;

Nitschke, Patrick ;

Belkadi, Aziz ;

Itan, Yuval ;

Boisson, Bertrand ;

Jabot-Hanin, Fabienne ;

Picard, Capucine ;

Bustamante, Jacinta ;

Eidenschenk, Celine ;

Boucherit, Soraya ;

Aladjidi, Nathalie ;

Lacombe, Didier ;

Barat, Pascal ;

Qasim, Waseem ;

Hurst, Jane A. ;

Pollard, Andrew J. ;

Uhlig, Holm H. ;

Fieschi, Claire ;

Michon, Jean ;

Bermudez, Vladimir P. ;

Abel, Laurent ;

de Villartay, Jean-Pierre ;

Geissmann, Frederic ;

Tangye, Stuart G. ;

Hurwitz, Jerard ;

Vivier, Eric ;

Casanova, Jean-Laurent ;

Smogorzewska, Agata ;

Jouanguy, Emmanuelle .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (05) :1991-2006

[10] MICE DEFICIENT FOR P53 ARE DEVELOPMENTALLY NORMAL BUT SUSCEPTIBLE TO SPONTANEOUS TUMORS [J].

DONEHOWER, LA ;

HARVEY, M ;

SLAGLE, BL ;

MCARTHUR, MJ ;

MONTGOMERY, CA ;

BUTEL, JS ;

BRADLEY, A .

NATURE, 1992, 356 (6366) :215-221

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