MLH1_MOUSE
ID MLH1_MOUSE Reviewed; 760 AA.
AC Q9JK91; Q3TG77; Q62454;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=DNA mismatch repair protein Mlh1;
DE AltName: Full=MutL protein homolog 1;
GN Name=Mlh1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RA Kumaran M., Rao M.R.S.;
RT "Cloning of the cDNA of the MutL homolog, MLH1 from mouse testis.";
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Heart;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-151.
RX PubMed=8674118; DOI=10.1016/s0092-8674(00)81312-4;
RA Edelmann W., Cohen P.E., Kane M., Lau K., Morrow B., Bennett S., Umar A.,
RA Kunkel T., Cattoretti G., Chaganti R., Pollard J.W., Kolodner R.D.,
RA Kucherlapati R.;
RT "Meiotic pachytene arrest in MLH1-deficient mice.";
RL Cell 85:1125-1134(1996).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=30949703; DOI=10.1093/nar/gkz226;
RA Liu H., Huang T., Li M., Li M., Zhang C., Jiang J., Yu X., Yin Y.,
RA Zhang F., Lu G., Luo M.C., Zhang L.R., Li J., Liu K., Chen Z.J.;
RT "SCRE serves as a unique synaptonemal complex fastener and is essential for
RT progression of meiosis prophase I in mice.";
RL Nucleic Acids Res. 47:5670-5683(2019).
CC -!- FUNCTION: Heterodimerizes with Pms2 to form MutL alpha, a component of
CC the post-replicative DNA mismatch repair system (MMR). DNA repair is
CC initiated by MutS alpha (Msh2-Msh6) or MutS beta (MSH2-MSH3) binding to
CC a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex.
CC Assembly of the MutL-MutS-heteroduplex ternary complex in presence of
CC RFC and PCNA is sufficient to activate endonuclease activity of Pms2.
CC It introduces single-strand breaks near the mismatch and thus generates
CC new entry points for the exonuclease EXO1 to degrade the strand
CC containing the mismatch. DNA methylation would prevent cleavage and
CC therefore assure that only the newly mutated DNA strand is going to be
CC corrected. MutL alpha (Mlh1-Pms2) interacts physically with the clamp
CC loader subunits of DNA polymerase III, suggesting that it may play a
CC role to recruit the DNA polymerase III to the site of the MMR. Also
CC implicated in DNA damage signaling, a process which induces cell cycle
CC arrest and can lead to apoptosis in case of major DNA damages.
CC Heterodimerizes with Mlh3 to form MutL gamma which plays a role in
CC meiosis (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Component of the DNA mismatch repair (MMR) complex composed at
CC least of MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer of MLH1 and PMS2
CC (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma).
CC Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-
CC MSH3). Part of the BRCA1-associated genome surveillance complex (BASC),
CC which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-
CC MRE11-NBS1 protein complex. This association could be a dynamic process
CC changing throughout the cell cycle and within subnuclear domains.
CC Interacts with MCM9; the interaction recruits MLH1 to chromatin.
CC Interacts MCM8. Interacts with PMS2. Interacts with MBD4. Interacts
CC with EXO1. Interacts with MTMR15/FAN1. {ECO:0000250|UniProtKB:P40692}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P40692}.
CC Chromosome {ECO:0000269|PubMed:30949703}. Note=Recruited to chromatin
CC in a MCM9-dependent manner. {ECO:0000250|UniProtKB:P40692}.
CC -!- SIMILARITY: Belongs to the DNA mismatch repair MutL/HexB family.
CC {ECO:0000305}.
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DR EMBL; AF250844; AAF64514.1; -; mRNA.
DR EMBL; AK168849; BAE40671.1; -; mRNA.
DR EMBL; U60872; AAC52672.1; -; Genomic_DNA.
DR EMBL; U59881; AAC52672.1; JOINED; Genomic_DNA.
DR EMBL; U59882; AAC52672.1; JOINED; Genomic_DNA.
DR EMBL; U59883; AAC52672.1; JOINED; Genomic_DNA.
DR EMBL; U59884; AAC52672.1; JOINED; Genomic_DNA.
DR CCDS; CCDS40784.1; -.
DR RefSeq; NP_001311451.1; NM_001324522.1.
DR RefSeq; NP_081086.2; NM_026810.2.
DR AlphaFoldDB; Q9JK91; -.
DR SMR; Q9JK91; -.
DR BioGRID; 201435; 1.
DR STRING; 10090.ENSMUSP00000035079; -.
DR GlyConnect; 2261; 1 N-Linked glycan (1 site).
DR GlyGen; Q9JK91; 1 site, 1 N-linked glycan (1 site).
DR iPTMnet; Q9JK91; -.
DR PhosphoSitePlus; Q9JK91; -.
DR EPD; Q9JK91; -.
DR MaxQB; Q9JK91; -.
DR PaxDb; Q9JK91; -.
DR PeptideAtlas; Q9JK91; -.
DR PRIDE; Q9JK91; -.
DR ProteomicsDB; 252576; -.
DR Antibodypedia; 4599; 822 antibodies from 45 providers.
DR DNASU; 17350; -.
DR Ensembl; ENSMUST00000035079; ENSMUSP00000035079; ENSMUSG00000032498.
DR GeneID; 17350; -.
DR KEGG; mmu:17350; -.
DR UCSC; uc009rvp.2; mouse.
DR CTD; 4292; -.
DR MGI; MGI:101938; Mlh1.
DR VEuPathDB; HostDB:ENSMUSG00000032498; -.
DR eggNOG; KOG1979; Eukaryota.
DR GeneTree; ENSGT00800000124177; -.
DR HOGENOM; CLU_004131_2_0_1; -.
DR InParanoid; Q9JK91; -.
DR OMA; ANYHVKK; -.
DR OrthoDB; 735423at2759; -.
DR PhylomeDB; Q9JK91; -.
DR TreeFam; TF300493; -.
DR Reactome; R-MMU-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
DR BioGRID-ORCS; 17350; 6 hits in 109 CRISPR screens.
DR ChiTaRS; Mlh1; mouse.
DR PRO; PR:Q9JK91; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q9JK91; protein.
DR Bgee; ENSMUSG00000032498; Expressed in undifferentiated genital tubercle and 245 other tissues.
DR ExpressionAtlas; Q9JK91; baseline and differential.
DR Genevisible; Q9JK91; MM.
DR GO; GO:0005712; C:chiasma; IDA:MGI.
DR GO; GO:0005694; C:chromosome; IDA:UniProtKB.
DR GO; GO:0000793; C:condensed chromosome; IDA:MGI.
DR GO; GO:0000794; C:condensed nuclear chromosome; IDA:MGI.
DR GO; GO:0005715; C:late recombination nodule; IDA:MGI.
DR GO; GO:0001673; C:male germ cell nucleus; IDA:MGI.
DR GO; GO:0032300; C:mismatch repair complex; IBA:GO_Central.
DR GO; GO:0032389; C:MutLalpha complex; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0000795; C:synaptonemal complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; IBA:GO_Central.
DR GO; GO:0140664; F:ATP-dependent DNA damage sensor activity; IEA:InterPro.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0032137; F:guanine/thymine mispair binding; IGI:MGI.
DR GO; GO:0032407; F:MutSalpha complex binding; ISO:MGI.
DR GO; GO:0003697; F:single-stranded DNA binding; ISO:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IMP:MGI.
DR GO; GO:0006281; P:DNA repair; IMP:MGI.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IMP:MGI.
DR GO; GO:0016321; P:female meiosis chromosome segregation; IMP:MGI.
DR GO; GO:0007129; P:homologous chromosome pairing at meiosis; IMP:MGI.
DR GO; GO:0045143; P:homologous chromosome segregation; IMP:MGI.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:MGI.
DR GO; GO:0045190; P:isotype switching; IMP:MGI.
DR GO; GO:0007060; P:male meiosis chromosome segregation; IMP:MGI.
DR GO; GO:0007140; P:male meiotic nuclear division; IMP:MGI.
DR GO; GO:0051321; P:meiotic cell cycle; IDA:MGI.
DR GO; GO:0045132; P:meiotic chromosome segregation; IMP:MGI.
DR GO; GO:0043060; P:meiotic metaphase I plate congression; IMP:MGI.
DR GO; GO:0051257; P:meiotic spindle midzone assembly; IMP:MGI.
DR GO; GO:0045141; P:meiotic telomere clustering; IMP:MGI.
DR GO; GO:0006298; P:mismatch repair; IDA:MGI.
DR GO; GO:0045950; P:negative regulation of mitotic recombination; IMP:MGI.
DR GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; IMP:MGI.
DR GO; GO:0048477; P:oogenesis; IMP:MGI.
DR GO; GO:0048298; P:positive regulation of isotype switching to IgA isotypes; IMP:CAFA.
DR GO; GO:0048304; P:positive regulation of isotype switching to IgG isotypes; IMP:CAFA.
DR GO; GO:0007131; P:reciprocal meiotic recombination; IMP:MGI.
DR GO; GO:0000712; P:resolution of meiotic recombination intermediates; IMP:MGI.
DR GO; GO:0009617; P:response to bacterium; IEP:MGI.
DR GO; GO:0016446; P:somatic hypermutation of immunoglobulin genes; IMP:MGI.
DR GO; GO:0016447; P:somatic recombination of immunoglobulin gene segments; IMP:MGI.
DR GO; GO:0002204; P:somatic recombination of immunoglobulin genes involved in immune response; IGI:MGI.
DR GO; GO:0007283; P:spermatogenesis; IMP:MGI.
DR Gene3D; 3.30.230.10; -; 1.
DR Gene3D; 3.30.565.10; -; 1.
DR InterPro; IPR014762; DNA_mismatch_repair_CS.
DR InterPro; IPR002099; DNA_mismatch_repair_N.
DR InterPro; IPR013507; DNA_mismatch_S5_2-like.
DR InterPro; IPR036890; HATPase_C_sf.
DR InterPro; IPR032189; Mlh1_C.
DR InterPro; IPR038973; MutL/Mlh/Pms.
DR InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
DR InterPro; IPR014721; Ribosomal_S5_D2-typ_fold_subgr.
DR PANTHER; PTHR10073; PTHR10073; 1.
DR Pfam; PF01119; DNA_mis_repair; 1.
DR Pfam; PF16413; Mlh1_C; 1.
DR SMART; SM01340; DNA_mis_repair; 1.
DR SUPFAM; SSF54211; SSF54211; 1.
DR SUPFAM; SSF55874; SSF55874; 1.
DR TIGRFAMs; TIGR00585; mutl; 1.
DR PROSITE; PS00058; DNA_MISMATCH_REPAIR_1; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell cycle; Chromosome; DNA damage; DNA repair;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome.
FT CHAIN 1..760
FT /note="DNA mismatch repair protein Mlh1"
FT /id="PRO_0000178001"
FT REGION 354..375
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 400..488
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 412..654
FT /note="Interaction with EXO1"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT COMPBIAS 421..435
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 472..487
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 38
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT BINDING 63
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT BINDING 82..84
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT BINDING 100..104
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT MOD_RES 481
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P40692"
FT CONFLICT 390
FT /note="E -> D (in Ref. 1; AAF64514)"
FT /evidence="ECO:0000305"
FT CONFLICT 404
FT /note="G -> V (in Ref. 1; AAF64514)"
FT /evidence="ECO:0000305"
FT CONFLICT 528
FT /note="M -> I (in Ref. 1; AAF64514)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 760 AA; 84670 MW; B789D812F497FDF7 CRC64;
MAFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTNIQVV VKEGGLKLIQ
IQDNGTGIRK EDLDIVCERF TTSKLQTFED LASISTYGFR GEALASISHV AHVTITTKTA
DGKCAYRASY SDGKLQAPPK PCAGNQGTLI TVEDLFYNII TRRKALKNPS EEYGKILEVV
GRYSIHNSGI SFSVKKQGET VSDVRTLPNA TTVDNIRSIF GNAVSRELIE VGCEDKTLAF
KMNGYISNAN YSVKKCIFLL FINHRLVESA ALRKAIETVY AAYLPKNTHP FLYLSLEISP
QNVDVNVHPT KHEVHFLHEE SILQRVQQHI ESKLLGSNSS RMYFTQTLLP GLAGPSGEAA
RPTTGVASSS TSGSGDKVYA YQMVRTDSRE QKLDAFLQPV SSLGPSQPQD PAPVRGARTE
GSPERATRED EEMLALPAPA EAAAESENLE RESLMETSDA AQKAAPTSSP GSSRKRHRED
SDVEMVENAS GKEMTAACYP RRRIINLTSV LSLQEEISER CHETLREMLR NHSFVGCVNP
QWALAQHQTK LYLLNTTKLS EELFYQILIY DFANFGVLRL SEPAPLFDLA MLALDSPESG
WTEDDGPKEG LAEYIVEFLK KKAEMLADYF SVEIDEEGNL IGLPLLIDSY VPPLEGLPIF
ILRLATEVNW DEEKECFESL SKECAMFYSI RKQYILEEST LSGQQSDMPG STSKPWKWTV
EHIIYKAFRS HLLPPKHFTE DGNVLQLANL PDLYKVFERC
