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Overview

Uniprot ID	P40692
Protein Name	DNA mismatch repair protein Mlh1
Gene Name	MLH1
Organism	Homo sapiens

Kla Sites from experimental identification

Position	Flanking peptide
123	TTKTADGKCAYRASY

Function

Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis

Protein Sequence

10 MSFVAGVIRR 20 LDETVVNRIA 30 AGEVIQRPAN 40 AIKEMIENCL 50 DAKSTSIQVI 60 VKEGGLKLIQ 70 IQDNGTGIRK 80 EDLDIVCERF 90 TTSKLQSFED 100 LASISTYGFR 110 GEALASISHV 120 AHVTITTKTA 130 DGKCAYRASY 140 SDGKLKAPPK 150 PCAGNQGTQI 160 TVEDLFYNIA 170 TRRKALKNPS 180 EEYGKILEVV 190 GRYSVHNAGI 200 SFSVKKQGET 210 VADVRTLPNA 220 STVDNIRSIF 230 GNAVSRELIE 240 IGCEDKTLAF 250 KMNGYISNAN 260 YSVKKCIFLL 270 FINHRLVEST 280 SLRKAIETVY 290 AAYLPKNTHP 300 FLYLSLEISP 310 QNVDVNVHPT 320 KHEVHFLHEE 330 SILERVQQHI 340 ESKLLGSNSS 350 RMYFTQTLLP 360 GLAGPSGEMV 370 KSTTSLTSSS 380 TSGSSDKVYA 390 HQMVRTDSRE 400 QKLDAFLQPL 410 SKPLSSQPQA 420 IVTEDKTDIS 430 SGRARQQDEE 440 MLELPAPAEV 450 AAKNQSLEGD 460 TTKGTSEMSE 470 KRGPTSSNPR 480 KRHREDSDVE 490 MVEDDSRKEM 500 TAACTPRRRI 510 INLTSVLSLQ 520 EEINEQGHEV 530 LREMLHNHSF 540 VGCVNPQWAL 550 AQHQTKLYLL 560 NTTKLSEELF 570 YQILIYDFAN 580 FGVLRLSEPA 590 PLFDLAMLAL 600 DSPESGWTEE 610 DGPKEGLAEY 620 IVEFLKKKAE 630 MLADYFSLEI 640 DEEGNLIGLP 650 LLIDNYVPPL 660 EGLPIFILRL 670 ATEVNWDEEK 680 ECFESLSKEC 690 AMFYSIRKQY 700 ISEESTLSGQ 710 QSEVPGSIPN 720 SWKWTVEHIV 730 YKALRSHILP 740 PKHFTEDGNI 750 LQLANLPDLY KVFERC

Gene Ontology

Classification	GO ID	Description
Cellular Component	GO:0005712	chiasma
Cellular Component	GO:0005694	chromosome
Cellular Component	GO:0005715	late recombination nodule
Cellular Component	GO:0001673	male germ cell nucleus
Cellular Component	GO:0016020	membrane
Cellular Component	GO:0032389	MutLalpha complex
Cellular Component	GO:0005654	nucleoplasm
Cellular Component	GO:0005634	nucleus
Cellular Component	GO:0000795	synaptonemal complex
Molecular Function	GO:0005524	ATP binding
Molecular Function	GO:0016887	ATP hydrolysis activity
Molecular Function	GO:0140664	ATP-dependent DNA damage sensor activity
Molecular Function	GO:0003682	chromatin binding
Molecular Function	GO:0008047	enzyme activator activity
Molecular Function	GO:0019899	enzyme binding
Molecular Function	GO:0032137	guanine/thymine mispair binding
Biological Process	GO:0000710	meiotic mismatch repair
Biological Process	GO:0006298	mismatch repair
Biological Process	GO:0048298	positive regulation of isotype switching to IgA isotypes
Biological Process	GO:0048304	positive regulation of isotype switching to IgG isotypes
Biological Process	GO:0016446	somatic hypermutation of immunoglobulin genes

Reference

[1] Yang D, Yin J, Shan L, Yi X, Zhang W et al.. Identification of lysine-lactylated substrates in gastric cancer cells.. iScience 25(7):104630. 2022 Jul 15. PMID: 35800753.

[2] He C, Zhang J, Bai X, Lu C, Zhang K. Lysine lactylation-based insight to understanding the characterization of cervical cancer.. Biochim Biophys Acta Mol Basis Dis 1870(7):167356. 2024 Oct. PMID: 39025375.

[3] He J, Lai T, Zhou Z, Yang H, Lei Z et al.. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.. Sci Rep 15(1):24651. 2025 Jul 9. PMID: 40634431.