HMCES_MOUSE
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 03-AUG-2022, entry version 115.
DE RecName: Full=Abasic site processing protein HMCES {ECO:0000305};
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).
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). The HMCES DNA-protein cross-link is
CC then degraded by the proteasome (By similarity). Promotes error-free
CC repair of abasic sites by acting as a 'suicide' enzyme that is
CC degraded, thereby protecting abasic sites from translesion synthesis
CC (TLS) polymerases and endonucleases that are error-prone and would
CC generate mutations and double-strand breaks (By similarity). Has
CC preference for ssDNA, but can also accommodate double-stranded DNA with
CC 3' or 5' overhang (dsDNA), and dsDNA-ssDNA 3' junction (By similarity).
CC Also involved in class switch recombination (CSR) in B-cells
CC independently of the formation of a DNA-protein cross-link: acts by
CC binding and protecting ssDNA overhangs to promote DNA double-strand
CC break repair through the microhomology-mediated alternative-end-joining
CC (Alt-EJ) pathway (PubMed:31806351). Acts as a protease: mediates
CC autocatalytic processing of its N-terminal methionine in order to
CC expose the catalytic cysteine (PubMed:29020633).
CC {ECO:0000250|UniProtKB:Q96FZ2, ECO:0000269|PubMed:29020633,
CC ECO:0000269|PubMed:31806351}.
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: Glu-127 is involved in sensing abasic sites in single-stranded
CC DNA (ssDNA). His-209 stabilizes the abasic sites by forming a hydrogen
CC bond with the O4' hydroxyl group. {ECO:0000250|UniProtKB:P76318}.
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). {ECO:0000269|PubMed:29020633,
CC ECO:0000269|PubMed:31806351}.
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 STRING; 10090.ENSMUSP00000032141; -.
DR iPTMnet; Q8R1M0; -.
DR PhosphoSitePlus; Q8R1M0; -.
DR SwissPalm; Q8R1M0; -.
DR EPD; Q8R1M0; -.
DR jPOST; Q8R1M0; -.
DR MaxQB; Q8R1M0; -.
DR PaxDb; Q8R1M0; -.
DR PeptideAtlas; Q8R1M0; -.
DR PRIDE; Q8R1M0; -.
DR ProteomicsDB; 267049; -.
DR Antibodypedia; 55718; 141 antibodies from 19 providers.
DR DNASU; 232210; -.
DR Ensembl; ENSMUST00000032141; ENSMUSP00000032141; ENSMUSG00000030060.
DR Ensembl; ENSMUST00000113606; ENSMUSP00000109236; ENSMUSG00000030060.
DR GeneID; 232210; -.
DR KEGG; mmu:232210; -.
DR UCSC; uc009cuh.1; mouse.
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; WVTCSVI; -.
DR OrthoDB; 1487237at2759; -.
DR PhylomeDB; Q8R1M0; -.
DR TreeFam; TF324343; -.
DR BioGRID-ORCS; 232210; 3 hits in 74 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 252 other tissues.
DR ExpressionAtlas; Q8R1M0; baseline and differential.
DR Genevisible; Q8R1M0; MM.
DR GO; GO:0005657; C:replication fork; ISS:UniProtKB.
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:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0097681; P:double-strand break repair via alternative nonhomologous end joining; IDA:UniProtKB.
DR GO; GO:0045830; P:positive regulation of isotype switching; IDA:UniProtKB.
DR GO; GO:0018142; P:protein-DNA covalent cross-linking; ISO:MGI.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 3.90.1680.10; -; 1.
DR InterPro; IPR003738; SRAP.
DR InterPro; IPR036590; SRAP-like.
DR PANTHER; PTHR13604; PTHR13604; 1.
DR Pfam; PF02586; SRAP; 1.
DR SUPFAM; SSF143081; SSF143081; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Chromosome; Covalent protein-DNA linkage;
KW DNA damage; DNA-binding; Hydrolase; Isopeptide bond; 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 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
