Download Gene Section MRE11A (MRE11 meiotic recombination 11 homolog A (S. cerevisiae))

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in Oncology and Haematology
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Gene Section
Mini Review
MRE11A (MRE11 meiotic recombination 11
homolog A (S. cerevisiae))
Nancy Uhrhammer
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU)
Published in Atlas Database: May 2004
Online updated version : http://AtlasGeneticsOncology.org/Genes/MRE11ID247.html
DOI: 10.4267/2042/38094
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
All tissues examined, with higher levels in proliferating
tissues.
Mre11 participates in the repair of DNA double-strand
breaks and replication errors as well as in meiotic
homologous recombination. The R/M/N complex is
part of the BRCA1-associated genome surveillance
complex (BASC). The phosphorylation of Mre11 and
NBS1 by another member of this super-complex,
ATM, is essential for an early step in the response to
DNA double-strand breaks (DSBs) and for their repair
by either non-homologous end joining (NHEJ) or
homologous recombination (HR). The interaction of
DNA end-bound Mre11 with Ku70 may direct the
break to rejoining by NHEJ, while the absense of Ku70
favors repair by HR. Current models propose DSB
detection by R/M/N is required for the activation of
ATM, which in turn phosphorylates Mre11 and NBS1,
thus placing Mre11 both upstream and downstream of
ATM in the DNA damage response signal transduction
cascade.
A mechanism has been proposed in which each end of
a DNA DSB is bound by an R/M/N dimer, the two
dimers being held to each other via the Zinc-hook
domain of each Rad50 unit. As the Zinc-hook of Rad50
is located at the end of a long coiled-coil domain, this
provides a flexible structure in which each DNA end is
accessible to additional repair enzymes while being
held in close proximity to each other in preparation for
re-ligation.
Cells lacking Mre11 are deficient in DSB repair, and
exhibit hypersensitivity to DNA damaging agents such
as ionizing radiation and radiomimetic drugs. Such
cells also have abnormal DNA replication and high
levels of chromosomal instability.
Localisation
Homology
Nuclear.
The gene is conserved throughout eukaryotes, with
70% nucleic acid homology to S. cerevisiea Mre11.
Other names: MRE11; ATLD: HNGS1
HGNC (Hugo): MRE11A
Location: 11q21
Note
Pseudogenes have been localized to chromosomes 3q25
and 7q11.2-q11.3.
DNA/RNA
Description
22 exons spanning 76 kb.
Transcription
Two isoforms are expressed, isoform 1 at 4772nt;
isoform 2, 4688 nt, transcribed from an alternative first
(noncoding) exon and lacking exon 5.
Protein
Description
Both isoforms are approximately 80 kDa. Isoform 1
includes 708 amino acids; isoform 2 includes 680.
Molecular studies of Mre11 typically do not distinguish
between the different isoforms. Mre11 is a subunit of
the Rad50/Mre11/NBS1 (R/M/N) complex and serves
as a single-strand DNA endonuclease, a 3' to 5' DNA
exonuclease, and to open hairpin DNA structures.
Expression
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3)
208
MRE11A MRE11 meiotic recombination 11 homolog A (S. cerevisiae)
Uhrhammer N
Cytogenetics
Spontaneous chromatid/chromosome breaks; non
clonal stable chromosome rearrangements involving
immunoglobulin
superfamily
genes
e.g.
inv(7)(p14q35); clonal rearrangements.
Mutations
Germinal
The hypomorphic arg633ter, asn117ser and arg571ter
alleles have been described in ATLD patients.
Homozygosity for null alleles is thought to be lethal in
embryogenesis, as is the case in Mre11 knockout mice.
Germline mutations have also been found in sporadic
hematopoetic malignancies, with loss of the wild-type
allele in the malignant cells.
References
Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR,
Weaver DT. Isolation and characterization of the human
MRE11 homologue. Genomics. 1995 Sep 1;29(1):80-6
Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI,
Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM. The
DNA double-strand break repair gene hMRE11 is mutated in
individuals with an ataxia-telangiectasia-like disorder. Cell.
1999 Dec 10;99(6):577-87
Somatic
Rare mutations have been found in breast cancer and
lymphoma. In colon cancers not expressing Mre11, the
mutation of a poly-T tract in intron 4 has been shown to
induce a splicing error that truncates the protein. Seven
of 20 gastric tumors failed to express Mre11, although
the cause of this was not demonstrated.
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC,
a super complex of BRCA1-associated proteins involved in the
recognition and repair of aberrant DNA structures. Genes Dev.
2000 Apr 15;14(8):927-39
Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D,
Gottesman M, Carroll D, Gautier J. Mre11 protein complex
prevents
double-strand
break
accumulation
during
chromosomal DNA replication. Mol Cell. 2001 Jul;8(1):137-47
Implicated in
Ataxia telangiectasia - like disorder
(ATLD)
Fukuda T, Sumiyoshi T, Takahashi M, Kataoka T, Asahara T,
Inui H, Watatani M, Yasutomi M, Kamada N, Miyagawa K.
Alterations of the double-strand break repair gene MRE11 in
cancer. Cancer Res. 2001 Jan 1;61(1):23-6
Disease
Ataxia telangiectasia-like disorder is a progressive
cerebellar degenerative disease with telangiectasia,
immunodeficiency, cancer risk, radiosensitivity, and
chromosomal instability. Only a very few ATLD
patients are known, in spite of the suggestion that as
many as 6% of "A-T" patients may in fact have
mutations in Mre11 (this figure is calculated be
comparing the size (and thus the opportunity for
mutation) of the two genes, as well as the observation
that a small minority of A-T patients express apparently
normal ATM and for whom no ATM mutation has
been detected). The two disorders cannot be
distinguished by their phenotypes, though there is some
indication that ATLD may have a milder course. The
severity of the disease may be dependent on the
residual activity of the mutated Mre11 alleles.
Prognosis
Poor, though the course of the disease may be milder
than found in classic A-T.
Falck J, Petrini JH, Williams BR, Lukas J, Bartek J. The DNA
damage-dependent intra-S phase checkpoint is regulated by
parallel pathways. Nat Genet. 2002 Mar;30(3):290-4
Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A,
Ottini L, Crescenzi M, Martinotti S, Bignami M, Frati L,
Screpanti I, Gulino A. Human MRE11 is inactivated in
mismatch repair-deficient cancers. EMBO Rep. 2002
Mar;3(3):248-54
Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen
BA, Karcher A, Henderson B, Bodmer JL, McMurray CT,
Carney JP, Petrini JH, Tainer JA. The Rad50 zinc-hook is a
structure joining Mre11 complexes in DNA recombination and
repair. Nature. 2002 Aug 1;418(6897):562-6
Giannini G, Rinaldi C, Ristori E, Ambrosini MI, Cerignoli F, Viel
A, Bidoli E, Berni S, D'Amati G, Scambia G, Frati L, Screpanti
I, Gulino A. Mutations of an intronic repeat induce impaired
MRE11 expression in primary human cancer with microsatellite
instability. Oncogene. 2004 Apr 8;23(15):2640-7
This article should be referenced as such:
Uhrhammer N. MRE11A (MRE11 meiotic recombination 11
homolog A (S. cerevisiae)). Atlas Genet Cytogenet Oncol
Haematol. 2004; 8(3):208-209.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3)
209