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The MRE11 complex: at the crossroads of DNA repair and checkpoint signalling

Nature Reviews Molecular Cell Biology volume 3, pages 317–327 (2002)Cite this article

Abstract

The Mre11 complex is a multisubunit nuclease that is composed of Mre11, Rad50 and Nbs1/Xrs2. Mutations in the genes that encode components of this complex result in DNA- damage sensitivity, genomic instability, telomere shortening and aberrant meiosis. The molecular defect that underlies these phenotypes has long been thought to be related to a DNA repair deficiency. However, recent studies have uncovered functions for the Mre11 complex in checkpoint signalling and DNA replication.

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Figure 1: Components of the Mre11 complex.
Figure 2: Architecture of the Mre11 complex.
Figure 3: The DNA end-bridging activity of Rad50.
Figure 4: Functional organization of DNA-damage-induced checkpoint signalling in eukaryotes.
Figure 5: Model for the role of the Mre11 complex in DNA-damage signalling.

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Acknowledgements

We apologize to our colleagues whose work could not be cited due to space restrictions. We thank members of the Jackson laboratory for helpful discussions. D.D. was supported by scholarships from the Conseil de Recherche en Science Naturelle et en Génie (CRSNG) du Canada, from the Fond pour la Formation de Chercheurs et l'Aide à la Recherche du Québec (Fonds FCAR) and from Cancer Research UK (CRUK). The S.P.J. laboratory is supported by grants from CRUK.

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Authors and Affiliations

  1. Wellcome Trust and Cancer Research UK Institute of Cancer and Developmental Biology, and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK

    Damien D'Amours & Stephen P. Jackson

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  1. Damien D'Amours
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Correspondence to Stephen P. Jackson.

Related links

Related links

DATABASES

Interpro

BRCT

FHA domain

OMIM

ataxia-telangiectasia

Nijmegen breakage syndrome

<i>Saccharomyces</i> Genome Database

Dnl4

Lif1

MRE11

RAD1

Rad10

Rad14

RAD27

RAD50

RAD52

Smc1

SPO13

SRS2

Tel1

XRS2

Swiss-Prot

bacteriophage T4 gp47

Cdc25A

Chk2

H2AX

KU70

Mre11

Nbs1

p21waf1

PCNA

rad32

TERT

Trf2

Glossary

EPISTATIC

Mutations that are epistatic mask the phenotype of each other.

HYPOMORPHIC MUTATION

A mutation that does not completely inactivate the product of a gene.

STRAND-DISSOCIATION ACTIVITY

The activity of a protein that facilitates the dissociation of complementary strands of a duplex DNA molecule.

STRAND-ANNEALING ACTIVITY

The activity of a protein that facilitates the formation of duplex DNA from complementary single-stranded DNA molecules.

PHOSPHOESTERASE MOTIFS

Short, evolutionarily conserved amino-acid sequences that confer an ability to hydrolyse phosphoester bonds.

EXONUCLEASE

An enzyme that catalyses the stepwise removal of mononucleotides from the termini of a DNA molecule.

ENDONUCLEASE

An enzyme that catalyses the degradation of phosphodiester bonds within a DNA molecule.

WALKER A AND B MOTIFS

Short, evolutionarily conserved amino-acid sequences that confer nucleotide-binding activity.

ABC?UVRA SUPERFAMILY

A family of proteins that contain the ATP-binding cassette (ABC), which couples ATP-dependent energy production with conformational changes in proteins.

NON-HOMOLOGOUS END-JOINING

The joining of two DNA ends that share little or no sequence homology. Also known as illegitimate recombination.

HOMOLOGOUS RECOMBINATION

A multistep process that leads to a homology-dependent association between two distinct DNA molecules.

DNA LIGASE

An enzyme that catalyses the joining of DNA molecules with 5′-phosphate- and 3′-hydroxyl-ended termini.

PML BODIES

Discrete nuclear substructures that contain many proteins, including the promyelocytic leukaemia (PML) protein.

V(D)J RECOMBINATION

The recombination between variable (V), diversity (D) and joining (J) segments of an immunoglobulin gene locus.

CLASS-SWITCH RECOMBINATION

The recombination between the repetitive switch (S) sequences of the constant (C) region of an immunoglobulin gene locus.

ATAXIA-TELANGIECTASIA, MUTATED

(ATM). A protein kinase that phosphorylates various proteins in response to DNA double-strand breaks to bring about cell-cycle arrest.

LESION-BYPASS DNA SYNTHESIS

Mutation-prone replication through DNA lesions that otherwise block the normal progression of the replication fork.

NUCLEOTIDE-EXCISION REPAIR

(NER). The pathway that is responsible for the removal of bulky, helix-distorting lesions in DNA.

ALU REPEAT

A dispersed, intermediately repetitive, 300-bp DNA sequence. There are 1,000,000 copies of Alu repeats in the human genome.

EPISTASIS GROUP

The genetic interaction between a group of genes, in which the effects of an allele of one member gene of the group hide the effects of alleles of other genes in the group.

DNA HELICASE

An enzyme that catalyses DNA-strand dissociation in a duplex DNA molecule.

INTRA-S PHASE CHECKPOINT

The mechanism that orchestrates the cellular response to DNA damage during S phase. A defective intra-S phase checkpoint is also known as radioresistant DNA synthesis (RDS) in mammalian cells.

TELOMERASE

Reverse-transcriptase-like DNA polymerase that is responsible for the elongation of chromosome ends.

TYPE-II SURVIVORS

Telomerase-deficient cells that amplify telomere repeats at the ends of their chromosomes by a Rad52-dependent, Rad51-independent recombination mechanism.

T-LOOPS

Large duplex loops that sequester chromosome extremities.

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D'Amours, D., Jackson, S. The MRE11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3, 317–327 (2002). https://doi.org/10.1038/nrm805

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