Mre11 Protein Complex Prevents Double-Strand Break Accumulation during Chromosomal DNA Replication
Open accessAbstract
Mre11 complex promotes repair of DNA double-strand breaks (DSBs). Xenopus Mre11 (X-Mre11) has been cloned, and its role in DNA replication and DNA damage checkpoint studied in cell-free extracts. DSBs stimulate the phosphorylation and 3'-5' exonuclease activity of X-Mre11 complex. This induced phosphorylation is ATM independent. Phosphorylated X-Mre11 is found associated with replicating nuclei. X-Mre11 complex is required to yield normal DNA replication products. Genomic DNA replicated in extracts immunodepleted of X-Mre11 complex accumulates DSBs as demonstrated by TUNEL assay and reactivity to phosphorylated histone H2AX antibodies. In contrast, the ATM-dependent DNA damage checkpoint that blocks DNA replication initiation is X-Mre11 independent. These results strongly suggest that the function of X-Mre11 complex is to repair DSBs that arise during normal DNA replication, thus unraveling a critical link between recombination-dependent repair and DNA replication.
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Cites
DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139
Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S., & Bonner, W. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.10.5858 · Cited by 5,438 · see citing works
The DNA damage response: putting checkpoints in perspective
Zhou, B.-B. S., & Elledge, S. J. (2000) · Nature · doi:10.1038/35044005 · Cited by 3,213 · see citing works
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785 · see citing works
Hartwell, L. H., & Kastan, M. B. (1994) · Science · doi:10.1126/science.7997877 · Cited by 2,523 · see citing works
Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo
Rogakou, E. P., Boon, C., Redon, C., & Bonner, W. M. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.5.905 · Cited by 2,422 · see citing works
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00610-2 · Cited by 2,098 · see citing works
Carney, J. P., Maser, R. S., Olivares, H., Davis, E. M., Le Beau, M., Yates, J. R., Hays, L., Morgan, W. F., & Petrini, J. H. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81175-7 · Cited by 1,226 · see citing works
Stewart, G. S., Maser, R. S., Stankovic, T., Bressan, D. A., Kaplan, M. I., Jaspers, N. G. J., Raams, A., Byrd, P. J., Petrini, J. H. J., & Taylor, A. M. R. (1999) · Cell · doi:10.1016/s0092-8674(00)81547-0 · Cited by 1,060 · see citing works
The importance of repairing stalled replication forks
Cox, M. M., Goodman, M. F., Kreuzer, K. N., Sherratt, D. J., Sandler, S. J., & Marians, K. J. (2000) · Nature · doi:10.1038/35003501 · Cited by 1,044 · see citing works
(1999) · PubMed · Cited by 1,030 · see citing works
<i>ATR</i> disruption leads to chromosomal fragmentation and early embryonic lethality
Brown, E. J., & Baltimore, D. (2000) · Genes & Development · doi:10.1101/gad.14.4.397 · Cited by 951 · see citing works
Chapter 30 Cell Cycle Extracts
Murray, A. W. (1991) · Methods in cell biology · doi:10.1016/s0091-679x(08)60298-8 · Cited by 942 · see citing works
The 3′ to 5′ Exonuclease Activity of Mre11 Facilitates Repair of DNA Double-Strand Breaks
Paull, T. T., & Gellert, M. F. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80097-0 · Cited by 919 · see citing works
Site-Specific Ribose Methylation of Preribosomal RNA: A Novel Function for Small Nucleolar RNAs
Kiss-László, Z., Henry, Y. A. L., Bachellerie, J., Caizergues‐Ferrer, M., & Kiss, T. (1996) · Cell · doi:10.1016/s0092-8674(00)81308-2 · Cited by 855 · see citing works
ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
Lim, D.-S., Kim, S.-T., Xu, B., Maser, R. S., Lin, J., Petrini, J. H. J., & Kastan, M. B. (2000) · Nature · doi:10.1038/35007091 · Cited by 786 · see citing works
Lee, S. E., Moore, J. K., Holmes, A. M., Umezu, K., Kolodner, R. D., & Haber, J. E. (1998) · Cell · doi:10.1016/s0092-8674(00)81482-8 · Cited by 775 · see citing works
Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex
Paull, T. T., & Gellert, M. (1999) · Genes & Development · doi:10.1101/gad.13.10.1276 · Cited by 551 · see citing works
RuvAB Acts at Arrested Replication Forks
Seigneur, M., Bidnenko, V., Ehrlich, S. D., & Michel, B. (1998) · Cell · doi:10.1016/s0092-8674(00)81772-9 · Cited by 538 · see citing works
Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products
Zhao, S., Weng, Y., Yuan, S. F., Lin, Y.-T., Hsu, H.-C., Lin, S. J., Gerbino, E., Song, M., Zdzienicka, M. Z., Gatti, R. A., et al. (2000) · Nature · doi:10.1038/35013083 · Cited by 483 · see citing works
ATAXIA-TELANGIECTASIA AND THE NIJMEGEN BREAKAGE SYNDROME: Related Disorders But Genes Apart
Shiloh, Y. (1997) · Annual Review of Genetics · doi:10.1146/annurev.genet.31.1.635 · Cited by 482 · see citing works
ATM-dependent phosphorylation of nibrin in response to radiation exposure
Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., & Khanna, K. (2000) · Nature Genetics · doi:10.1038/75508 · Cited by 468 · see citing works
ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response
Wu, X., Ranganathan, V., Weisman, D., Heine, W. F., Ciccone, D. N., O'Neill, T. B., Crick, K. E., Pierce, K. A., Lane, W. S., Rathbun, G. A., et al. (2000) · Nature · doi:10.1038/35013089 · Cited by 446 · see citing works
Moreau, S., Ferguson, J. R., & Symington, L. S. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.1.556 · Cited by 445 · see citing works
Nuclease Activities in a Complex of Human Recombination and DNA Repair Factors Rad50, Mre11, and p95
Trujillo, K. M., Yuan, S. F., Lee, E. Y.-H. P., & Sung, P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.34.21447 · Cited by 417 · see citing works
Luo, G., Yao, M. S., Bender, C. F., Mills, M., Bladl, A. R., Bradley, A., & Petrini, J. H. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7376 · Cited by 408 · see citing works
Haber, J. E. (1998) · Cell · doi:10.1016/s0092-8674(00)81626-8 · Cited by 407 · see citing works
DNA Damage-Dependent Nuclear Dynamics of the Mre11 Complex
Mirzoeva, O. K., & Petrini, J. H. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.1.281-288.2001 · Cited by 387 · see citing works
Zhu, J., Petersen, S., Tessarollo, L., & Nussenzweig, A. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00019-7 · Cited by 374 · see citing works
Knippers, R. (1970) · Nature · doi:10.1038/2281050a0 · Cited by 323 · see citing works
Response to RAG-Mediated V(D)J Cleavage by NBS1 and γ-H2AX
Chen, H. T., Bhandoola, A., Difilippantonio, M. J., Zhu, J., Brown, M. J., Tai, X., Rogakou, E. P., Brotz, T. M., Bonner, W. M., Ried, T., et al. (2000) · Science · doi:10.1126/science.290.5498.1962 · Cited by 318 · see citing works
Xiao, Y. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.15.2985 · Cited by 316 · see citing works
Cephalic expression and molecular characterization of Xenopus En-2
Hemmati‐Brivanlou, A., de la Torre, J. R., Holt, C. E., & Harland, R. M. (1991) · Development · doi:10.1242/dev.111.3.715 · Cited by 288 · see citing works
Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells
Yamaguchi‐Iwai, Y., Sonoda, E., Sasaki, M. S., Morrison, C., Haraguchi, T., Hiraoka, Y., Yamashita, Y. M., Yagi, T., Takata, M., Price, C., et al. (1999) · The EMBO Journal · doi:10.1093/emboj/18.23.6619 · Cited by 282 · see citing works
Bressan, D. A., Baxter, B. K., & Petrini, J. H. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.11.7681 · Cited by 271 · see citing works
Holliday Junctions Accumulate in Replication Mutants via a RecA Homolog-Independent Mechanism
Zou, H., & Rothstein, R. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80316-5 · Cited by 256 · see citing works
The Mre11 complex and ATM: collaborating to navigate S phase
Petrini, J. H. J. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00091-0 · Cited by 228 · see citing works
Dolganov, G. M., Maser, R. S., Novikov, A., Tosto, L., Chong, S., Bressan, D. A., & Petrini, J. H. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4832 · Cited by 224 · see citing works
A developmental timer that regulates apoptosis at the onset of gastrulation
Hensey, C. E., & Gautier, J. (1997) · Mechanisms of Development · doi:10.1016/s0925-4773(97)00191-3 · Cited by 192 · see citing works
Self-citationCostanzo, V., Robertson, K. M.-P., Ying, C. Y., Kim, E., Avvedimento, E. V., Gottesman, M. E., Grieco, D., & Gautier, J. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00063-0 · Cited by 176 · see citing works
Self-citationChin, G. M., & Villeneuve, A. M. (2001) · Genes & Development · doi:10.1101/gad.864101 · Cited by 161 · see citing works
Alteration of N-Terminal Phosphoesterase Signature Motifs Inactivates Saccharomyces cerevisiae Mre11
Bressan, D. A., Olivares, H. A., Nelms, B. E., & Petrini, J. H. J. (1998) · Genetics · doi:10.1093/genetics/150.2.591 · Cited by 140 · see citing works
Isolation and Characterization of the Human MRE11 Homologue
Petrini, J. H. J., Walsh, M. E., DiMare, C., Chen, X., Korenberg, J. R., & Weaver, D. T. (1995) · Genomics · doi:10.1006/geno.1995.1217 · Cited by 132 · see citing works
The Nijmegen Breakage Syndrome Protein Is Essential for Mre11 Phosphorylation upon DNA Damage
Dong, Z., Zhong, Q., & Chen, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19513 · Cited by 118 · see citing works
RuvABC‐dependent double‐strand breaks in dnaBts mutants require RecA
Seigneur, M., Ehrlich, S. D., & Michel, B. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.02152.x · Cited by 118 · see citing works
Tavassoll, M., Shayeghl, M., Nasim, A., & Watts, F. Z. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.3.383 · Cited by 108 · see citing works
Limoli, C. L., Giedzinski, E., Morgan, W. F., & Cleaver, J. E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130182897 · Cited by 98 · see citing works
Girard, P.-M., Foray, N., Stümm, M., Waugh, A. P. W., Riballo, E., Maser, R. S., Phillips, W. P., Petrini, J. H. J., Arlett, C. F., & Jeggo, P. A. (2000) · PubMed · Cited by 72 · see citing works
Functions of the yeast meiotic recombination genes, MRE11 and MRE2
Ogawa, H. (1995) · Advances in Biophysics · doi:10.1016/0065-227x(95)99383-z · Cited by 70 · see citing works
DNA polymerase stalling, sister chromatid recombination and the BRCA genes
Scully, R., Puget, N., & Vlasáková, K. (2000) · Oncogene · doi:10.1038/sj.onc.1203971 · Cited by 68 · see citing works
Protein Kinase A is required for chromosomal DNA replication
Costanzo, V., Avvedimento, E. V., Gottesman, M. E., et al. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80395-9 · Cited by 29 · see citing works
Self-citationRobertson, K. M.-P., Hensey, C. E., & Gautier, J. (1999) · Oncogene · doi:10.1038/sj.onc.1203194 · Cited by 28 · see citing works
Self-citationCharacterization of FEN-1 from Xenopus laevis
Bibikova, M. V., Wu, B., Chi, E., Kim, K.-H., Trautman, J. K., & Carroll, D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.34222 · Cited by 13 · see citing works
Self-citationRegulation of cell cycle progression following DNA damage
Hensey, C. E., & Gautier, J. (1995) · Springer eBooks · doi:10.1007/978-1-4615-1809-9_12 · Cited by 11 · see citing works
Self-citation
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ATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798 · see citing works
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., & Jackson, S. P. (2006) · Nature Cell Biology · doi:10.1038/ncb1337 · Cited by 1,064 · see citing works
The MRE11 complex: at the crossroads of DNA repair and checkpoint signalling
D'Amours, D., & Jackson, S. P. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm805 · Cited by 874 · see citing works
The MRE11 complex: starting from the ends
Stracker, T. H., & Petrini, J. H. J. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3047 · Cited by 734 · see citing works
Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer
Vilenchik, M. M., & Knudson, A. G. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2135498100 · Cited by 717 · see citing works
DNA double-strand break repair: From mechanistic understanding to cancer treatment
HELLEDAY, T., LO, J., VANGENT, D., & ENGELWARD, B. (2007) · DNA Repair · doi:10.1016/j.dnarep.2007.02.006 · Cited by 640 · see citing works
The Mre11 complex is required for ATM activation and the G2/M checkpoint
Carson, C. T., Schwartz, R. A., Stracker, T. H., Lilley, C. E., Lee, D. V., & Weitzman, M. D. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg630 · Cited by 502 · see citing works
Mendrysa, S. M., McElwee, M. K., Michalowski, J., O'Leary, K. A., Young, K. M., & Perry, M. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.2.462-473.2003 · Cited by 234 · see citing works
Cancer predisposition and hematopoietic failure in <i> Rad50 <sup>S/S</sup> </i> mice
Bender, C. F., Sikes, M. L., Sullivan, R., Huye, L. E., Le Beau, M. M., Roth, D. B., Mirzoeva, O. K., Oltz, E. M., & Petrini, J. H. J. (2002) · Genes & Development · doi:10.1101/gad.1007902 · Cited by 213 · see citing works
Mechanisms of replication fork protection: a safeguard for genome stability
Errico, A., & Costanzo, V. (2012) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2012.655374 · Cited by 159 · see citing works
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Duursma, A. M., Driscoll, R., Elias, J. E., & Cimprich, K. A. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.03.006 · Cited by 153 · see citing works
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Alt, J. R., Bouska, A., Fernandez, M. R., Cerny, R. L., Xiao, H., & Eischen, C. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413387200 · Cited by 131 · see citing works
Mechanisms of eukaryotic DNA double strand break repair
Cahill, D. (2006) · Frontiers in bioscience · doi:10.2741/1938 · Cited by 129 · see citing works
Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway
Nakada, D., Hirano, Y., & Sugimoto, K. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.22.10016-10025.2004 · Cited by 113 · see citing works
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Self-citationOh, K.-S., Bustin, M., Mazur, S. J., Appella, E., & Kraemer, K. H. (2011) · DNA Repair · doi:10.1016/j.dnarep.2010.09.004 · Cited by 60 · see citing works
Di Virgilio, M., Ying, C. Y., & Gautier, J. (2009) · DNA Repair · doi:10.1016/j.dnarep.2009.07.006 · Cited by 52 · see citing works
Self-citation
- Authors
- Costanzo, V., Robertson, K., Bibikova, M., Kim, E., Grieco, D., Gottesman, M., Carroll, D., & Gautier, J.
- Affiliations
- Columbia University (US)
- University of Utah (US)
- University of Naples Federico II (IT)
- Corresponding author
- Gautier, Jean
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2001-07
- Volume
- 8
- Issue
- 1
- Pages
- 137-147
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2099518892
- Cited by
- 239
- References
- 53
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 5 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 14 · 2012: 9
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Funders
- National Institutes of Health (5r01gm056781-04)
- National Institute of General Medical Sciences (R01 GM56781)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Mre11 complex, DNA double-strand break repair, DNA replication, DNA damage checkpoint, 3'-5' exonuclease activity, H2AX phosphorylation, Xenopus, cell-free extracts
- MeSH terms
- MRE11 Homologue Protein, Amino Acid Sequence, Animals, Antifungal Agents, Caffeine, Cell Cycle, Cell Nucleus, Cell-Free System, Chromatin, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, Humans, Models, Biological, Molecular Sequence Data, Oocytes, Phosphodiesterase Inhibitors, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Pyrans, Recombinant Proteins, Spiro Compounds, Xenopus laevis, Immunoblotting, In Situ Nick-End Labeling
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