ID HMCES_MOUSE Reviewed; 353 AA.
AC Q8R1M0;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 27-MAR-2024, entry version 123.
DE RecName: Full=Abasic site processing protein HMCES {ECO:0000305};
DE EC=4.-.-.- {ECO:0000250|UniProtKB:Q96FZ2};
DE AltName: Full=Embryonic stem cell-specific 5-hydroxymethylcytosine-binding protein;
DE Short=ES cell-specific 5hmC-binding protein;
DE AltName: Full=Peptidase HMCES {ECO:0000305};
DE EC=3.4.-.- {ECO:0000269|PubMed:29020633};
DE AltName: Full=SRAP domain-containing protein 1 {ECO:0000303|PubMed:29020633};
GN Name=Hmces {ECO:0000303|PubMed:31806351, ECO:0000312|MGI:MGI:1914053};
GN Synonyms=Srap1 {ECO:0000303|PubMed:29020633},
GN Srapd1 {ECO:0000312|MGI:MGI:1914053};
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 [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Mammary gland, and Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP CAUTION, AND DNA-BINDING.
RX PubMed=23434322; DOI=10.1016/j.cell.2013.02.004;
RA Spruijt C.G., Gnerlich F., Smits A.H., Pfaffeneder T., Jansen P.W.,
RA Bauer C., Munzel M., Wagner M., Muller M., Khan F., Eberl H.C.,
RA Mensinga A., Brinkman A.B., Lephikov K., Muller U., Walter J., Boelens R.,
RA van Ingen H., Leonhardt H., Carell T., Vermeulen M.;
RT "Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized
RT derivatives.";
RL Cell 152:1146-1159(2013).
RN [3]
RP FUNCTION, TISSUE SPECIFICITY, CLEAVAGE OF INITIATOR METHIONINE, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF CYS-2; HIS-209 AND 289-TRP-LEU-290.
RX PubMed=29020633; DOI=10.1016/j.celrep.2017.09.055;
RA Kweon S.M., Zhu B., Chen Y., Aravind L., Xu S.Y., Feldman D.E.;
RT "Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease.";
RL Cell Rep. 21:482-494(2017).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=31806351; DOI=10.1016/j.molcel.2019.10.031;
RA Shukla V., Halabelian L., Balagere S., Samaniego-Castruita D.,
RA Feldman D.E., Arrowsmith C.H., Rao A., Aravind L.;
RT "HMCES functions in the alternative end-joining pathway of the DNA DSB
RT repair during class switch recombination in B cells.";
RL Mol. Cell 0:0-0(2019).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=35450882; DOI=10.1101/gad.349438.122;
RA Wu L., Shukla V., Yadavalli A.D., Dinesh R.K., Xu D., Rao A., Schatz D.G.;
RT "HMCES protects immunoglobulin genes specifically from deletions during
RT somatic hypermutation.";
RL Genes Dev. 36:433-450(2022).
CC -!- FUNCTION: Sensor of abasic sites in single-stranded DNA (ssDNA)
CC required to preserve genome integrity by promoting error-free repair of
CC abasic sites (By similarity). Acts as an enzyme that recognizes and
CC binds abasic sites in ssDNA at replication forks and chemically
CC modifies the lesion by forming a covalent cross-link with DNA: forms a
CC stable thiazolidine linkage between a ring-opened abasic site and the
CC alpha-amino and sulfhydryl substituents of its N-terminal catalytic
CC cysteine residue (By similarity). Promotes error-free repair by
CC protecting abasic sites from translesion synthesis (TLS) polymerases
CC and endonucleases that are error-prone and would generate mutations and
CC double-strand breaks (By similarity). The HMCES DNA-protein cross-link
CC is then either reversed or degraded (By similarity). HMCES is able to
CC catalyze the reversal of its thiazolidine cross-link and cycle between
CC a cross-link and a non-cross-linked state depending on DNA context:
CC mediates self-reversal of the thiazolidine cross-link in double
CC stranded DNA, allowing APEX1 to initiate downstream repair of abasic
CC sites (By similarity). The HMCES DNA-protein cross-link can also be
CC degraded by the SPRTN metalloprotease following unfolding by the
CC BRIP1/FANCJ helicase (By similarity). Has preference for ssDNA, but can
CC also accommodate double-stranded DNA with 3' or 5' overhang (dsDNA),
CC and dsDNA-ssDNA 3' junction (By similarity). Plays a protective role
CC during somatic hypermutation of immunoglobulin genes in B-cells: acts
CC via its ability to form covalent cross-links with abasic sites, thereby
CC limiting the accumulation of deletions in somatic hypermutation target
CC regions (PubMed:35450882). Also involved in class switch recombination
CC (CSR) in B-cells independently of the formation of a DNA-protein cross-
CC link: acts by binding and protecting ssDNA overhangs to promote DNA
CC double-strand break repair through the microhomology-mediated
CC alternative-end-joining (Alt-EJ) pathway (PubMed:31806351). Acts as a
CC protease: mediates autocatalytic processing of its N-terminal
CC methionine in order to expose the catalytic cysteine (PubMed:29020633).
CC {ECO:0000250|UniProtKB:Q96FZ2, ECO:0000269|PubMed:29020633,
CC ECO:0000269|PubMed:31806351, ECO:0000269|PubMed:35450882}.
CC -!- ACTIVITY REGULATION: Formation and reversal of DNA-protein cross-link
CC depends on DNA context. Catalyzes formation of the thiazolidine linkage
CC in presence of abasic sites in single-stranded DNA. Mediates the
CC reversal of the thiazolidine cross-link in presence of double stranded
CC DNA. {ECO:0000250|UniProtKB:Q96FZ2}.
CC -!- SUBUNIT: Interacts (via PIP-box motif) with PCNA.
CC {ECO:0000250|UniProtKB:Q96FZ2}.
CC -!- SUBCELLULAR LOCATION: Chromosome {ECO:0000250|UniProtKB:Q96FZ2}.
CC Note=Recruited to chromatin following DNA damage. Localizes to
CC replication forks. {ECO:0000250|UniProtKB:Q96FZ2}.
CC -!- TISSUE SPECIFICITY: Expressed in embryonic stem cells.
CC {ECO:0000269|PubMed:29020633}.
CC -!- DOMAIN: The N-terminal catalytic Cys-2 residue forms a thiazolidine
CC linkage to a ring-opened DNA abasic site. Glu-127 catalyzes reversal of
CC the thiazolidine linkage; self-reversal is favoured by duplex DNA
CC formation (By similarity). Glu-127 is also involved in sensing abasic
CC sites in single-stranded DNA (ssDNA). His-209 stabilizes the abasic
CC sites by forming a hydrogen bond with the O4' hydroxyl group (By
CC similarity). {ECO:0000250|UniProtKB:P76318,
CC ECO:0000250|UniProtKB:Q96FZ2}.
CC -!- DISRUPTION PHENOTYPE: Embryonic sublethality and altered DNA
CC methylation, possibly caused by accumulation of 5-hydroxymethylcytosine
CC (5hmC) in genomic DNA (PubMed:29020633). Mice do not show defects in
CC hematopoiesis and no alterations in global 5hmC levels in bone marrow
CC cells (PubMed:31806351). In contrast, mice display a decrease in class
CC switch recombination (CSR) in mature activated B-cells
CC (PubMed:31806351). Increased deletions in germinal center B-cells
CC (PubMed:35450882). {ECO:0000269|PubMed:29020633,
CC ECO:0000269|PubMed:31806351, ECO:0000269|PubMed:35450882}.
CC -!- SIMILARITY: Belongs to the SOS response-associated peptidase family.
CC {ECO:0000305}.
CC -!- CAUTION: Was initially reported to specifically bind 5-
CC hydroxymethylcytosine (5hmC)-containing DNA in stem cells
CC (PubMed:23434322). It was later suggested to act as an endonuclease
CC that specifically cleaves 5hmC-containing DNA (PubMed:29020633).
CC However, recent studies question this activity: no alterations in
CC global 5hmC levels are observed in bone marrow cells from knockout mice
CC (PubMed:31806351). {ECO:0000269|PubMed:23434322,
CC ECO:0000269|PubMed:29020633, ECO:0000269|PubMed:31806351}.
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DR EMBL; BC024401; AAH24401.1; -; mRNA.
DR EMBL; BC064070; AAH64070.1; -; mRNA.
DR CCDS; CCDS39551.1; -.
DR RefSeq; NP_776098.1; NM_173737.2.
DR AlphaFoldDB; Q8R1M0; -.
DR SMR; Q8R1M0; -.
DR BioGRID; 231228; 2.
DR IntAct; Q8R1M0; 1.
DR STRING; 10090.ENSMUSP00000109236; -.
DR iPTMnet; Q8R1M0; -.
DR PhosphoSitePlus; Q8R1M0; -.
DR SwissPalm; Q8R1M0; -.
DR EPD; Q8R1M0; -.
DR jPOST; Q8R1M0; -.
DR MaxQB; Q8R1M0; -.
DR PaxDb; 10090-ENSMUSP00000032141; -.
DR PeptideAtlas; Q8R1M0; -.
DR ProteomicsDB; 267049; -.
DR Pumba; Q8R1M0; -.
DR Antibodypedia; 55718; 160 antibodies from 20 providers.
DR DNASU; 232210; -.
DR Ensembl; ENSMUST00000032141.14; ENSMUSP00000032141.8; ENSMUSG00000030060.15.
DR Ensembl; ENSMUST00000113606.2; ENSMUSP00000109236.2; ENSMUSG00000030060.15.
DR GeneID; 232210; -.
DR KEGG; mmu:232210; -.
DR UCSC; uc009cuh.1; mouse.
DR AGR; MGI:1914053; -.
DR CTD; 56941; -.
DR MGI; MGI:1914053; Hmces.
DR VEuPathDB; HostDB:ENSMUSG00000030060; -.
DR eggNOG; KOG2618; Eukaryota.
DR GeneTree; ENSGT00390000018439; -.
DR HOGENOM; CLU_035990_1_0_1; -.
DR InParanoid; Q8R1M0; -.
DR OMA; SYNKGPQ; -.
DR OrthoDB; 204678at2759; -.
DR PhylomeDB; Q8R1M0; -.
DR TreeFam; TF324343; -.
DR BioGRID-ORCS; 232210; 3 hits in 79 CRISPR screens.
DR ChiTaRS; Hmces; mouse.
DR PRO; PR:Q8R1M0; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q8R1M0; Protein.
DR Bgee; ENSMUSG00000030060; Expressed in animal zygote and 255 other cell types or tissues.
DR ExpressionAtlas; Q8R1M0; baseline and differential.
DR Genevisible; Q8R1M0; MM.
DR GO; GO:0005657; C:replication fork; ISS:UniProtKB.
DR GO; GO:0140431; F:DNA-(abasic site) binding; IEA:Ensembl.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0006974; P:DNA damage response; ISS:UniProtKB.
DR GO; GO:0097681; P:double-strand break repair via alternative nonhomologous end joining; IDA:UniProtKB.
DR GO; GO:0036297; P:interstrand cross-link repair; ISS:UniProtKB.
DR GO; GO:0045830; P:positive regulation of isotype switching; IDA:UniProtKB.
DR GO; GO:0106300; P:protein-DNA covalent cross-linking repair; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0016446; P:somatic hypermutation of immunoglobulin genes; IDA:UniProtKB.
DR Gene3D; 3.90.1680.10; SOS response associated peptidase-like; 1.
DR InterPro; IPR003738; SRAP.
DR InterPro; IPR036590; SRAP-like.
DR PANTHER; PTHR13604:SF0; ABASIC SITE PROCESSING PROTEIN HMCES; 1.
DR PANTHER; PTHR13604; DC12-RELATED; 1.
DR Pfam; PF02586; SRAP; 1.
DR SUPFAM; SSF143081; BB1717-like; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Chromosome; Covalent protein-DNA linkage;
KW DNA damage; DNA-binding; Hydrolase; Isopeptide bond; Lyase; Phosphoprotein;
KW Protease; Reference proteome; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:29020633"
FT CHAIN 2..353
FT /note="Abasic site processing protein HMCES"
FT /id="PRO_0000164395"
FT REGION 292..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 332..338
FT /note="PIP-box"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT COMPBIAS 336..353
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 2
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT ACT_SITE 127
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT SITE 127
FT /note="Required for sensing abasic sites"
FT /evidence="ECO:0000250|UniProtKB:P76318"
FT SITE 209
FT /note="Required to stabilize abasic sites"
FT /evidence="ECO:0000250|UniProtKB:P76318"
FT MOD_RES 2
FT /note="Thiazolidine linkage to a ring-opened DNA abasic
FT site"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT MOD_RES 160
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT MOD_RES 294
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT MOD_RES 321
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 148
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 151
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 274
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 275
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 305
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 339
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT CROSSLNK 342
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q96FZ2"
FT MUTAGEN 2
FT /note="C->A: Accumulation of uncleaved form with the N-
FT terminal methionine."
FT /evidence="ECO:0000269|PubMed:29020633"
FT MUTAGEN 209
FT /note="H->Q: Accumulation of uncleaved form with the N-
FT terminal methionine."
FT /evidence="ECO:0000269|PubMed:29020633"
FT MUTAGEN 289..290
FT /note="WL->GA: Stimulates cleavage of the N-terminal
FT methionine."
FT /evidence="ECO:0000269|PubMed:29020633"
SQ SEQUENCE 353 AA; 40169 MW; 3A34829AFD4603C2 CRC64;
MCGRTSCHLP REVLTRACAY QDRQGRRRLP QWRDPDKYCP SYNKSPQSSS PVLLSRLHFE
KDADSSDRII IPMRWGLVPS WFKESDPSKL QFNTTNCRSD TIMEKQSFKV PLGKGRRCVV
LADGFYEWQR CQGTNQRQPY FIYFPQIKTE KSGGNDASDS SDNKEKVWDN WRLLTMAGIF
DCWEAPGGEC LYSYSIITVD SCRGLSDIHS RMPAILDGEE AVSKWLDFGE VATQEALKLI
HPIDNITFHP VSPVVNNSRN NTPECLAPAD LLVKKEPKAN GSSQRMMQWL ATKSPKKEVP
DSPKKDASGL PQWSSQFLQK SPLPAKRGAT SSFLDRWLKQ EKEDEPMAKK PNS
//
