PRIPO_MOUSE
ID PRIPO_MOUSE Reviewed; 537 AA.
AC Q6P1E7; Q8BSR3;
DT 06-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=DNA-directed primase/polymerase protein {ECO:0000303|PubMed:24207056};
DE EC=2.7.7.- {ECO:0000269|PubMed:29073063};
GN Name=Primpol {ECO:0000303|PubMed:24207056, ECO:0000312|MGI:MGI:3603756};
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] (ISOFORM 2).
RC STRAIN=C57BL/6J;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Brain;
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 [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=24207056; DOI=10.1016/j.molcel.2013.09.025;
RA Garcia-Gomez S., Reyes A., Martinez-Jimenez M.I., Chocron E.S., Mouron S.,
RA Terrados G., Powell C., Salido E., Mendez J., Holt I.J., Blanco L.;
RT "PrimPol, an archaic primase/polymerase operating in human cells.";
RL Mol. Cell 52:541-553(2013).
RN [4]
RP FUNCTION.
RX PubMed=26926109; DOI=10.1093/nar/gkw123;
RA Pilzecker B., Buoninfante O.A., Pritchard C., Blomberg O.S., Huijbers I.J.,
RA van den Berk P.C., Jacobs H.;
RT "PrimPol prevents APOBEC/AID family mediated DNA mutagenesis.";
RL Nucleic Acids Res. 44:4734-4744(2016).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=29073063; DOI=10.1073/pnas.1705367114;
RA Torregrosa-Munumer R., Forslund J.M.E., Goffart S., Pfeiffer A.,
RA Stojkovic G., Carvalho G., Al-Furoukh N., Blanco L., Wanrooij S.,
RA Pohjoismaeki J.L.O.;
RT "PrimPol is required for replication reinitiation after mtDNA damage.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:11398-11403(2017).
CC -!- FUNCTION: DNA primase and DNA polymerase required to tolerate
CC replication-stalling lesions by bypassing them (PubMed:26926109,
CC PubMed:29073063). Required to facilitate mitochondrial and nuclear
CC replication fork progression by initiating de novo DNA synthesis using
CC dNTPs and acting as an error-prone DNA polymerase able to bypass
CC certain DNA lesions (By similarity). Shows a high capacity to tolerate
CC DNA damage lesions such as 8oxoG and abasic sites in DNA (By
CC similarity). Provides different translesion synthesis alternatives when
CC DNA replication is stalled: able to synthesize DNA primers downstream
CC of lesions, such as ultraviolet (UV) lesions, R-loops and G-
CC quadruplexes, to allow DNA replication to continue (By similarity). Can
CC also realign primers ahead of 'unreadable lesions' such as abasic sites
CC and 6-4 photoproduct (6-4 pyrimidine-pyrimidinone), thereby skipping
CC the lesion (By similarity). Also able to incorporate nucleotides
CC opposite DNA lesions such as 8oxoG, like a regular translesion
CC synthesis DNA polymerase (By similarity). Also required for
CC reinitiating stalled forks after UV damage during nuclear DNA
CC replication (By similarity). Required for mitochondrial DNA (mtDNA)
CC synthesis and replication, by reinitiating synthesis after UV damage or
CC in the presence of chain-terminating nucleotides (PubMed:29073063).
CC Prevents APOBEC family-mediated DNA mutagenesis by repriming downstream
CC of abasic site to prohibit error-prone translesion synthesis
CC (PubMed:26926109). Has non-overlapping function with POLH (By
CC similarity). In addition to its role in DNA damage response, also
CC required to maintain efficient nuclear and mitochondrial DNA
CC replication in unperturbed cells (By similarity).
CC {ECO:0000250|UniProtKB:Q96LW4, ECO:0000269|PubMed:26926109,
CC ECO:0000269|PubMed:29073063}.
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q96LW4};
CC Note=Can act both with Mn(2+) and Mg(2+) as cofactor in vitro, but
CC Mn(2+) is the preferred cofactor in vivo. The polymerase activity
CC incorporates correct dNTPs with much higher efficiency with Mn(2+) than
CC with Mg(2+). The fidelity is slightly more accurate when Mg(2+) is the
CC cofactor compared to Mn(2+). In the presence of Mn(2+), a
CC conformational transition step from non-productive to productive
CC PRIMPOL:DNA complexes limits the enzymatic turnover, whereas in the
CC presence of Mg(2+), the chemical step becomes rate limiting.
CC {ECO:0000250|UniProtKB:Q96LW4};
CC -!- SUBUNIT: Interacts with RPA1; leading to recruitment to chromatin and
CC stimulate DNA primase activity. Interacts with SSBP1. Interacts with
CC POLDIP2; leading to enhance DNA polymerase activity.
CC {ECO:0000250|UniProtKB:Q96LW4}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q96LW4}.
CC Mitochondrion matrix {ECO:0000250|UniProtKB:Q96LW4}. Chromosome
CC {ECO:0000250|UniProtKB:Q96LW4}. Note=Present in the nucleus, but a
CC larger fraction is localized inside mitochondria. Associates with
CC nuclear chromatin during the G1 and S phases of unperturbed cell
CC cycles. Recruited to stalled replication forks following interaction
CC with RPA1. {ECO:0000250|UniProtKB:Q96LW4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6P1E7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6P1E7-2; Sequence=VSP_023420, VSP_023421;
CC -!- DOMAIN: The zinc knuckle motif binds zinc and is required for the DNA
CC primase activity. It facilitates the binding and selection of the 5'-
CC nucleotide of the newly synthesized primer and the recognition of
CC preferred initiation sites. {ECO:0000250|UniProtKB:Q96LW4}.
CC -!- DOMAIN: The RPA1-binding motifs (RBM) mediate interaction with RPA1 and
CC are essential for recruitment to chromatin. The interaction is
CC primarily mediated by RPA1-binding motif 1, which binds to the basic
CC cleft of RPA1, with motif 2 plays a supporting role in RPA1-binding.
CC {ECO:0000250|UniProtKB:Q96LW4}.
CC -!- DOMAIN: The presence of an Asp-Aaa-Glu (DxE) motif in the metal-binding
CC active site favors the use of Mn(2+) ions to achieve optimal incoming
CC nucleotide stabilization, especially required during primer synthesis.
CC Glu-116 is required to stabilize the incoming nucleotide at the 3'-
CC site. {ECO:0000250|UniProtKB:Q96LW4}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable but show defects in mitochondrial
CC DNA synthesis. {ECO:0000269|PubMed:24207056}.
CC -!- SIMILARITY: Belongs to the eukaryotic-type primase small subunit
CC family. {ECO:0000305}.
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DR EMBL; AK030772; BAC27128.1; -; mRNA.
DR EMBL; BC065112; AAH65112.1; -; mRNA.
DR CCDS; CCDS40334.1; -. [Q6P1E7-1]
DR RefSeq; NP_001001184.1; NM_001001184.1. [Q6P1E7-1]
DR RefSeq; XP_006509521.1; XM_006509458.3. [Q6P1E7-1]
DR RefSeq; XP_006509522.1; XM_006509459.3. [Q6P1E7-1]
DR RefSeq; XP_006509523.1; XM_006509460.3. [Q6P1E7-1]
DR RefSeq; XP_006509527.1; XM_006509464.2.
DR RefSeq; XP_017168376.1; XM_017312887.1. [Q6P1E7-1]
DR AlphaFoldDB; Q6P1E7; -.
DR SMR; Q6P1E7; -.
DR BioGRID; 240480; 4.
DR STRING; 10090.ENSMUSP00000036119; -.
DR PhosphoSitePlus; Q6P1E7; -.
DR EPD; Q6P1E7; -.
DR MaxQB; Q6P1E7; -.
DR PaxDb; Q6P1E7; -.
DR PRIDE; Q6P1E7; -.
DR Antibodypedia; 66503; 35 antibodies from 10 providers.
DR Ensembl; ENSMUST00000040468; ENSMUSP00000036119; ENSMUSG00000038225. [Q6P1E7-1]
DR Ensembl; ENSMUST00000209787; ENSMUSP00000148093; ENSMUSG00000038225. [Q6P1E7-1]
DR Ensembl; ENSMUST00000211400; ENSMUSP00000147574; ENSMUSG00000038225. [Q6P1E7-1]
DR GeneID; 408022; -.
DR KEGG; mmu:408022; -.
DR UCSC; uc009lqi.1; mouse. [Q6P1E7-1]
DR CTD; 201973; -.
DR MGI; MGI:3603756; Primpol.
DR VEuPathDB; HostDB:ENSMUSG00000038225; -.
DR eggNOG; ENOG502QS1Q; Eukaryota.
DR GeneTree; ENSGT00390000003901; -.
DR HOGENOM; CLU_027838_0_0_1; -.
DR InParanoid; Q6P1E7; -.
DR OMA; ADWWMDA; -.
DR OrthoDB; 1373896at2759; -.
DR PhylomeDB; Q6P1E7; -.
DR TreeFam; TF328961; -.
DR BioGRID-ORCS; 408022; 5 hits in 106 CRISPR screens.
DR ChiTaRS; Primpol; mouse.
DR PRO; PR:Q6P1E7; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q6P1E7; protein.
DR Bgee; ENSMUSG00000038225; Expressed in dorsal pancreas and 179 other tissues.
DR ExpressionAtlas; Q6P1E7; baseline and differential.
DR Genevisible; Q6P1E7; MM.
DR GO; GO:0000428; C:DNA-directed RNA polymerase complex; IEA:UniProtKB-KW.
DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005657; C:replication fork; ISS:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0003896; F:DNA primase activity; IDA:UniProtKB.
DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; ISS:UniProtKB.
DR GO; GO:0030145; F:manganese ion binding; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0042276; P:error-prone translesion synthesis; ISS:UniProtKB.
DR GO; GO:0043504; P:mitochondrial DNA repair; IDA:UniProtKB.
DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB.
DR GO; GO:0062176; P:R-loop disassembly; ISS:UniProtKB.
DR GO; GO:0031297; P:replication fork processing; ISS:UniProtKB.
DR GO; GO:0009411; P:response to UV; ISS:UniProtKB.
DR GO; GO:0019985; P:translesion synthesis; ISS:UniProtKB.
DR InterPro; IPR044917; PRIMPOL.
DR PANTHER; PTHR31399; PTHR31399; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chromosome; Coiled coil; DNA damage; DNA repair;
KW DNA-directed DNA polymerase; DNA-directed RNA polymerase; Manganese;
KW Metal-binding; Mitochondrion; Nucleotidyltransferase; Nucleus;
KW Reference proteome; Transcription; Transferase; Zinc.
FT CHAIN 1..537
FT /note="DNA-directed primase/polymerase protein"
FT /id="PRO_0000279396"
FT REGION 462..536
FT /note="Interaction with RPA1"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT REGION 462..481
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 1..22
FT /evidence="ECO:0000255"
FT MOTIF 401..434
FT /note="Zinc knuckle motif"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT MOTIF 494..507
FT /note="RPA1-binding motif 1"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT MOTIF 524..532
FT /note="RPA1-binding motif 2"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT COMPBIAS 465..481
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 76
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 114..116
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 114
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 116
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 165..169
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 270..273
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 279
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 401
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 408
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 428
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT BINDING 433
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96LW4"
FT VAR_SEQ 314..328
FT /note="VSNVRFSDTLRVLTC -> ILRYSASSHMPPISD (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_023420"
FT VAR_SEQ 329..537
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_023421"
FT CONFLICT 110
FT /note="K -> R (in Ref. 1; BAC27128)"
FT /evidence="ECO:0000305"
FT CONFLICT 299
FT /note="S -> T (in Ref. 1; BAC27128)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 537 AA; 61330 MW; F44F0A18155AFB3F CRC64;
MLRKWEARVK QIEERASHYE RKPLSSVYRP RLAKPEEPSS IWKLFHRQNQ AFNFVKSCKE
SVHVFALECK RGNGQRIYLV TSYAQLWFYY KTRKTLLHCY EVIPENAVCK LYFDLEFNKL
ANPGADGKMM VALLIQHVCK ALEEFYNVQC SAEDVFNLDS STEEKFSRHL IFQLHNVAFK
DNRHAGNFVR KILQPALHLI AEDDEAKVPE AVGQDASGFS VTPLKQEISE AREKVGLPKQ
CDPDLSFLVV KNHMGEKCLF VDLGVYTKNR NFRLYQSSKI GKCVSLEVAE DNRFIPKQSK
DISEENQYFL SSLVSNVRFS DTLRVLTCHP SQTKRKRAEC FNSTGTSVES IEGFQGSPYP
EVDQFVLSLV NKHDIKGGIR RWNYFFPEEL LVYDICKYRW CENIGRAHKS NNIMILVDLK
NEVWYQKCHD PVCKAQNFKS TCSPLPTEVS LLFLLKDEDF TSGETDDTST SLTKDSQTPP
SCNLSAGGLS AAAWDDEDDA LFLEATEDAE FADAADKSLG SMDDIPDELI IEALQNS
