Reviewed, UniProtKB/Swiss-Prot P49959 (MRE11_HUMAN)

Names and origin

Protein names

Recommended name:
    Double-strand break repair protein MRE11A
Alternative name(s):
    MRE11 meiotic recombination 11 homolog A
    MRE11 homolog 1

Gene names

Name:	MRE11A
Synonyms:	HNGS1, MRE11

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	708 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11A. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11A to prevent nucleolytic degradation past a given point. The complex may also be required for DNA damage signaling via activation of the ATM kinase. In telomeres the MRN complex may modulate t-loop formation.
Cofactor	Manganese By similarity.
Subunit structure	Component of the MRN complex composed of two heterodimers RAD50/MRE11A associated with a single NBN. Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11A and NBN By similarity. Interacts with DCLRE1C/Artemis.
Subcellular location	Nucleus By similarity. Note: Localizes to discrete nuclear foci after treatment with genotoxic agents By similarity.
Post-translational modification	Phosphorylated upon DNA damage, probably by ATM or ATR. Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15
Involvement in disease	Defects in MRE11A are a cause of ataxia telangiectasia-like disorder (ATLD) [MIM:604391]. ATLD is a disease with the same clinical feature than ataxia-telangiectasia but with a somewhat milder clinical course. Ref.17 Defects in MRE11A may be a cause of breast cancer.
Miscellaneous	In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.
Sequence similarities	Belongs to the MRE11/RAD32 family.

Ontologies

Keywords
Biological process	DNA damage DNA repair Meiosis
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Ligand	Manganese
Molecular function	Endonuclease Exonuclease Hydrolase Nuclease
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	double-strand break repair via nonhomologous end joining Ref.4 Traceable author statement. Source: ProtInc reciprocal meiotic recombination Ref.1 Traceable author statement. Source: ProtInc regulation of mitotic recombination Ref.1 Traceable author statement. Source: ProtInc telomere maintenance via telomerase Traceable author statement. Source: ProtInc
Cellular component	nucleoplasm Ref.4 Traceable author statement. Source: ProtInc
Molecular function	3'-5' exonuclease activity Ref.4 Traceable author statement. Source: ProtInc double-stranded DNA binding Traceable author statement. Source: ProtInc manganese ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein C-terminus binding Inferred from physical interaction. Source: UniProtKB single-stranded DNA specific endodeoxyribonuclease activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCNE1	P24864	1	EBI-396513,EBI-519526
H2AFX	P16104	1	EBI-396513,EBI-494830
NBN	O60934	1	EBI-396513,EBI-494844

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P49959-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P49959-2)

The sequence of this isoform differs from the canonical sequence as follows:
     595-622: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 708	708	Double-strand break repair protein MRE11A		PRO_0000138672
Sites
	Active site	129	1	Proton donor By similarity
Amino acid modifications
	Modified residue	74	1	Phosphothreonine Ref.10
	Modified residue	649	1	Phosphoserine Ref.15
	Modified residue	678	1	Phosphoserine Ref.13
	Modified residue	688	1	Phosphoserine Ref.10 Ref.11 Ref.12 Ref.14 Ref.15
	Modified residue	689	1	Phosphoserine Ref.10 Ref.12 Ref.14 Ref.15
Natural variations
	Alternative sequence	595 – 622	28	Missing in isoform 2.		VSP_003262
	Natural variant	104	1	S → C in cancer. Ref.18		VAR_011625
	Natural variant	117	1	N → S in ATLD. Ref.17		VAR_008513
	Natural variant	157	1	M → V		VAR_011626
	Natural variant	237	1	F → C in a breast cancer sample; somatic mutation. Ref.20		VAR_036416
	Natural variant	302	1	H → Y in a breast cancer sample; somatic mutation. Ref.20		VAR_036417
	Natural variant	305	1	R → W in ovarian cancer. Ref.19		VAR_025528
	Natural variant	468	1	D → G: dbSNP rs1805367. Ref.6		VAR_019288
	Natural variant	503	1	R → H in cancer. Ref.18		VAR_011627
	Natural variant	572	1	R → Q in cancer. Ref.18		VAR_011628
	Natural variant	698	1	M → V: dbSNP rs1805362. Ref.6		VAR_019289
Experimental info
	Sequence conflict	31	1	V → A in AAC78721. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified September 26, 2001. Version 3. Checksum: D94ABFBDDF6106AD	FASTA	708	80,593
	10 20 30 40 50 60 MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD 70 80 90 100 110 120 LFHENKPSRK TLHTCLELLR KYCMGDRPVQ FEILSDQSVN FGFSKFPWVN YQDGNLNISI 130 140 150 160 170 180 PVFSIHGNHD DPTGADALCA LDILSCAGFV NHFGRSMSVE KIDISPVLLQ KGSTKIALYG 190 200 210 220 230 240 LGSIPDERLY RMFVNKKVTM LRPKEDENSW FNLFVIHQNR SKHGSTNFIP EQFLDDFIDL 250 260 270 280 290 300 VIWGHEHECK IAPTKNEQQL FYISQPGSSV VTSLSPGEAV KKHVGLLRIK GRKMNMHKIP 310 320 330 340 350 360 LHTVRQFFME DIVLANHPDI FNPDNPKVTQ AIQSFCLEKI EEMLENAERE RLGNSHQPEK 370 380 390 400 410 420 PLVRLRVDYS GGFEPFSVLR FSQKFVDRVA NPKDIIHFFR HREQKEKTGE EINFGKLITK 430 440 450 460 470 480 PSEGTTLRVE DLVKQYFQTA EKNVQLSLLT ERGMGEAVQE FVDKEEKDAI EELVKYQLEK 490 500 510 520 530 540 TQRFLKERHI DALEDKIDEE VRRFRETRQK NTNEEDDEVR EAMTRARALR SQSEESASAF 550 560 570 580 590 600 SADDLMSIDL AEQMANDSDD SISAATNKGR GRGRGRRGGR GQNSASRGGS QRGRADTGLE 610 620 630 640 650 660 TSTRSRNSKT AVSASRNMSI IDAFKSTRQQ PSRNVTTKNY SEVIEVDESD VEEDIFPTTS 670 680 690 700 KTDQRWSSTS SSKIMSQSQV SKGVDFESSE DDDDDPFMNT SSLRRNRR
	Isoform 2. Checksum: B36BA7EC8CE79BEE	FASTA	680	77,642
	10 20 30 40 50 60 MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD 70 80 90 100 110 120 LFHENKPSRK TLHTCLELLR KYCMGDRPVQ FEILSDQSVN FGFSKFPWVN YQDGNLNISI 130 140 150 160 170 180 PVFSIHGNHD DPTGADALCA LDILSCAGFV NHFGRSMSVE KIDISPVLLQ KGSTKIALYG 190 200 210 220 230 240 LGSIPDERLY RMFVNKKVTM LRPKEDENSW FNLFVIHQNR SKHGSTNFIP EQFLDDFIDL 250 260 270 280 290 300 VIWGHEHECK IAPTKNEQQL FYISQPGSSV VTSLSPGEAV KKHVGLLRIK GRKMNMHKIP 310 320 330 340 350 360 LHTVRQFFME DIVLANHPDI FNPDNPKVTQ AIQSFCLEKI EEMLENAERE RLGNSHQPEK 370 380 390 400 410 420 PLVRLRVDYS GGFEPFSVLR FSQKFVDRVA NPKDIIHFFR HREQKEKTGE EINFGKLITK 430 440 450 460 470 480 PSEGTTLRVE DLVKQYFQTA EKNVQLSLLT ERGMGEAVQE FVDKEEKDAI EELVKYQLEK 490 500 510 520 530 540 TQRFLKERHI DALEDKIDEE VRRFRETRQK NTNEEDDEVR EAMTRARALR SQSEESASAF 550 560 570 580 590 600 SADDLMSIDL AEQMANDSDD SISAATNKGR GRGRGRRGGR GQNSASRGGS QRGRAFKSTR 610 620 630 640 650 660 QQPSRNVTTK NYSEVIEVDE SDVEEDIFPT TSKTDQRWSS TSSSKIMSQS QVSKGVDFES 670 680 SEDDDDDPFM NTSSLRRNRR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterization of the human MRE11 homologue." Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R., Weaver D.T. Genomics 29:80-86(1995) [PubMed: 8530104] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[2]	Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R., Weaver D.T. Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO C-TERMINUS.
[3]	"Molecular cloning and functional characterization of hNGS1, a yeast and human MRE11 homolog." Chamankhah M., Wei Y., Xiao W. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks." Paull T.T., Gellert M. Mol. Cell 1:969-979(1998) [PubMed: 9651580] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay." Pitts S.A., Kullar H.S., Stankovic T., Stewart G.S., Last J.I.K., Bedenham T., Armstrong S.J., Piane M., Chessa L., Taylor A.M.R., Byrd P.J. Hum. Mol. Genet. 10:1155-1162(2001) [PubMed: 11371508] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[6]	NIEHS SNPs program Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-468 AND VAL-698.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[8]	"Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response." Zhang X., Succi J., Feng Z., Prithivirajsingh S., Story M.D., Legerski R.J. Mol. Cell. Biol. 24:9207-9220(2004) [PubMed: 15456891] [Abstract] Cited for: INTERACTION WITH DCLRE1C.
[9]	"Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage." Chen L., Morio T., Minegishi Y., Nakada S., Nagasawa M., Komatsu K., Chessa L., Villa A., Lecis D., Delia D., Mizutani S. Cancer Sci. 96:134-141(2005) [PubMed: 15723659] [Abstract] Cited for: INTERACTION WITH DCLRE1C.
[10]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-74; SER-688 AND SER-689, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"Global phosphoproteome of HT-29 human colon adenocarcinoma cells." Kim J.-E., Tannenbaum S.R., White F.M. J. Proteome Res. 4:1339-1346(2005) [PubMed: 16083285] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, MASS SPECTROMETRY.
[12]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, MASS SPECTROMETRY. Tissue: Epithelium.
[13]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-678, MASS SPECTROMETRY.
[14]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, MASS SPECTROMETRY.
[15]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-649; SER-688 AND SER-689, MASS SPECTROMETRY.
[16]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[17]	"The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder." 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. Cell 99:577-587(1999) [PubMed: 10612394] [Abstract] Cited for: VARIANT ATLD SER-117.
[18]	"Alterations of the double-strand break repair gene MRE11 in cancer." Fukuda T., Sumiyoshi T., Takahashi M., Kataoka T., Asahara T., Inui H., Watatani M., Yasutomi M., Kamada N., Miyagawa K. Cancer Res. 61:23-26(2001) [PubMed: 11196167] [Abstract] Cited for: VARIANTS CANCER CYS-104; HIS-503 AND GLN-572.
[19]	"Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility." Heikkinen K., Karppinen S.-M., Soini Y., Maekinen M., Winqvist R. J. Med. Genet. 40:E131-E131(2003) [PubMed: 14684699] [Abstract] Cited for: VARIANT OVARIAN CANCER TRP-305.
[20]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-237 AND TYR-302.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

MRE11base

MRE11A mutation db

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	U37359 mRNA. Translation: AAC78721.1. AF022778 mRNA. Translation: AAD10197.1. AF073362 mRNA. Translation: AAC36249.1. AF303395 , AF303379, AF303380, AF303381, AF303382, AF303383, AF303384, AF303385, AF303386, AF303387, AF303388, AF303389, AF303390, AF303391, AF303392, AF303393, AF303394 Genomic DNA. Translation: AAK18790.1. AY584241 Genomic DNA. Translation: AAS79320.1. BC063458 mRNA. Translation: AAH63458.1.
IPI	IPI00029159. IPI00218853.
RefSeq	NP_005582.1.
UniGene	Hs.192649
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	P49959. 5 interactions.
PTM databases
PhosphoSite	P49959.
Proteomic databases
PRIDE	P49959.
Genome annotation databases
Ensembl	ENSG00000020922. Homo sapiens. [Contig view]
GeneID	4361.
Organism-specific databases
GeneCards	GC11M093790.
H-InvDB	HIX0010030.
HGNC	HGNC:7230. MRE11A.
HPA	CAB004081. HPA002691.
MIM	600814. gene. 604391. phenotype.
PharmGKB	PA30934.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P49959.
HOVERGEN	P49959.
OMA	P49959. GEAVKKH.
Enzyme and pathway databases
Pathway_Interaction_DB	bard1pathway. BARD1 signaling events. telomerasepathway. Regulation of Telomerase.
Reactome	REACT_216. DNA Repair.
Gene expression databases
ArrayExpress	P49959.
Bgee	P49959.
CleanEx	HS_MRE11A.
GermOnline	ENSG00000020922. Homo sapiens.
Family and domain databases
InterPro	IPR003701. DNA_repair. IPR004843. M-pesterase. IPR007281. Mre11_DNA_bd. [Graphical view]
PANTHER	PTHR10139. DNA_repair. 1 hit.
Pfam	PF00149. Metallophos. 1 hit. PF04152. Mre11_DNA_bind. 1 hit. [Graphical view]
PIRSF	PIRSF000882. DSB_repair_MRE11. 1 hit.
TIGRFAMs	TIGR00583. mre11. 1 hit.
ProtoNet	Search...
Other Resources
NextBio	17163.
PMAP-CutDB	P49959.
SOURCE	Search...

Entry information

Entry name

MRE11_HUMAN

Accession

Primary (citable) accession number: P49959
Secondary accession number(s): O43475

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	September 26, 2001
Last modified:	June 16, 2009
This is version 100 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)