EMBO J. 2019 Apr 15;38(8). pii: e101496. doi: 10.15252/embj.2019101496. Epub 2019 Mar 26.
SUMOylation promotes protective responses to DNA-protein crosslinks.
Borgermann N1, Ackermann L1, Schwertman P1, Hendriks IA2, Thijssen K3, Liu JC1, Lans H3, Nielsen ML2, Mailand N4,5.
Abstract
DNA-protein
crosslinks (DPCs) are highly cytotoxic lesions that obstruct essential
DNA transactions and whose resolution is critical for cell and
organismal fitness. However, the mechanisms by which cells respond to
and overcome DPCs remain incompletely understood. Recent studies
unveiled a dedicated DPC repair pathway in higher eukaryotes involving
the SprT-type metalloprotease SPRTN/DVC1, which proteolytically
processes DPCs during DNA replication in a ubiquitin-regulated manner.
Here, we show that chemically induced and defined enzymatic DPCs trigger
potent chromatin SUMOylation responses targeting the crosslinked
proteins and associated factors. Consequently, inhibiting SUMOylation
compromises DPC clearance and cellular fitness. We demonstrate that
ACRC/GCNA family SprT proteases interact with SUMO and establish
important physiological roles of Caenorhabditis elegans GCNA-1
and SUMOylation in promoting germ cell and embryonic survival upon DPC
formation. Our findings provide first global insights into signaling
responses to DPCs and reveal an evolutionarily conserved function of
SUMOylation in facilitating responses to these lesions in metazoans that
may complement replication-coupled DPC resolution processes.
© 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
KEYWORDS:
SUMO ; DNA repair; DNA‐protein crosslinks; post‐translational modifications; proteomicsSPRTN (1q42.2) https://www.ncbi.nlm.nih.gov/gene/83932
- Also known as
- DVC1; PRO4323; spartan; C1orf124
- Summary The protein encoded by this gene may play a role in DNA repair during replication of damaged DNA. This protein recruits valosin containing protein (p97) to stalled DNA replication forks where it may prevent excessive translesional DNA synthesis and limit the number of DNA-damage induced mutations. It may also be involved in replication-related G2/M-checkpoint regulation. Deficiency of a similar protein in mouse causes chromosomal instability and progeroid phenotypes. Mutations in this gene have been associated with Ruijs-Aalfs syndrome (RJALS). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]
- Expression Broad expression in testis (RPKM 6.8), bone marrow (RPKM 3.1) and 24 other tissues See more
- Preferred Names
- sprT-like domain-containing protein Spartan
- Names
- DNA damage protein targeting VCP
- DNA damage-targeting VCP (p97) adaptor
- zinc finger RAD18 domain-containing protein
- Conserved Domains (2) summary
-
- smart00734
Location:453 → 476 - ZnF_Rad18; Rad18-like CCHC zinc finger
- pfam10263
Location:45 → 213 - SprT-like; SprT-like family
- smart00734
Related articles in PubMed
- DNA-dependent protease activity of human Spartan facilitates replication of DNA-protein crosslink-containing DNA. Mórocz M, et al. Nucleic Acids Res, 2017 Apr 7. PMID 28053116, Free PMC Article
- Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN. Stingele J, et al. Mol Cell, 2016 Nov 17. PMID 27871365, Free PMC Article
- DNA-protein crosslink repair: proteases as DNA repair enzymes. Stingele J, et al. Trends Biochem Sci, 2015 Feb. PMID 25496645
- Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Lessel D, et al. Nat Genet, 2014 Nov. PMID 25261934, Free PMC Article
- The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites. Toth A, et al. DNA Repair (Amst), 2017 Jan. PMID 27838458
GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?
- e show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)- a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs
- SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability.
- Loss of SPRTN results in failure to repair DNA-protein crosslinks (DPCs) and hypersensitivity to DPC-inducing agents.
- Spartan has a DNA-dependent protease activity degrading certain proteins bound to DNA.
- DNA binding by SPARTAN regulates the targeting of Poleta to damage sites after UV exposure, and this function contributes highly to its DNA-damage tolerance function.
- These findings offer new insights into the determinants of PIP box for PCNA binding.
- USP1, p21 and Spartan are translesion DNA synthesis regulators. (Review)
- Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.
- The results suggest that Spartan negatively regulates POLD3 function in Rev1/Pol zeta-dependent translesion synthesis.
- Spartan is recruited to sites of stalled replication via ubiquitinated PCNA and plays an ZNimportant role to prevent mutations associated with replication of damaged DNA.
sprT-like domain-containing protein Spartan isoform a [Homo sapiens]
NCBI Reference Sequence: NP_114407.3
LOCUS NP_114407 489 aa linear PRI 02-MAY-2019
DEFINITION sprT-like domain-containing protein Spartan isoform a [Homo
sapiens].
ACCESSION NP_114407
VERSION NP_114407.3
DBSOURCE REFSEQ: accession NM_032018.7
KEYWORDS RefSeq; MANE Select.
SOURCE Homo sapiens (human)
ORGANISM Homo sapiens
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
REFERENCE 1 (residues 1 to 489)
AUTHORS Morocz M, Zsigmond E, Toth R, Enyedi MZ, Pinter L and Haracska L.
TITLE DNA-dependent protease activity of human Spartan facilitates
replication of DNA-protein crosslink-containing DNA
JOURNAL Nucleic Acids Res. 45 (6), 3172-3188 (2017)
PUBMED 28053116
REMARK GeneRIF: Spartan has a DNA-dependent protease activity degrading
certain proteins bound to DNA.
REFERENCE 2 (residues 1 to 489)
AUTHORS Toth A, Hegedus L, Juhasz S, Haracska L and Burkovics P.
TITLE The DNA-binding box of human SPARTAN contributes to the targeting
of Poleta to DNA damage sites
JOURNAL DNA Repair (Amst.) 49, 33-42 (2017)
PUBMED 27838458
REMARK GeneRIF: DNA binding by SPARTAN regulates the targeting of Poleta
to damage sites after UV exposure, and this function contributes
highly to its DNA-damage tolerance function.
REFERENCE 3 (residues 1 to 489)
AUTHORS Vaz B, Popovic M, Newman JA, Fielden J, Aitkenhead H, Halder S,
Singh AN, Vendrell I, Fischer R, Torrecilla I, Drobnitzky N, Freire
R, Amor DJ, Lockhart PJ, Kessler BM, McKenna GW, Gileadi O and
Ramadan K.
TITLE Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled
DNA-Protein Crosslink Repair
JOURNAL Mol. Cell 64 (4), 704-719 (2016)
PUBMED 27871366
REMARK GeneRIF: SPRTN protease represents a specialized DNA
replication-coupled DPC repair pathway essential for DNA
replication progression and genome stability.
REFERENCE 4 (residues 1 to 489)
AUTHORS Stingele J, Bellelli R, Alte F, Hewitt G, Sarek G, Maslen SL,
Tsutakawa SE, Borg A, Kjaer S, Tainer JA, Skehel JM, Groll M and
Boulton SJ.
TITLE Mechanism and Regulation of DNA-Protein Crosslink Repair by the
DNA-Dependent Metalloprotease SPRTN
JOURNAL Mol. Cell 64 (4), 688-703 (2016)
PUBMED 27871365
REMARK GeneRIF: Loss of SPRTN results in failure to repair DNA-protein
crosslinks (DPCs) and hypersensitivity to DPC-inducing agents.
REFERENCE 5 (residues 1 to 489)
AUTHORS Lopez-Mosqueda J, Maddi K, Prgomet S, Kalayil S, Marinovic-Terzic
I, Terzic J and Dikic I.
TITLE SPRTN is a mammalian DNA-binding metalloprotease that resolves
DNA-protein crosslinks
JOURNAL Elife 5, e21491 (2016)
PUBMED 27852435
REMARK GeneRIF: e show that SPRTN is a DNA-dependent mammalian protease
required for resolving cytotoxic DNA-protein crosslinks (DPCs)- a
function that had only been attributed to the metalloprotease Wss1
in budding yeast. We provide genetic evidence that SPRTN and Wss1
function distinctly in vivo to resolve DPCs
Publication Status: Online-Only
REFERENCE 6 (residues 1 to 489)
AUTHORS Mosbech A, Gibbs-Seymour I, Kagias K, Thorslund T, Beli P, Povlsen
L, Nielsen SV, Smedegaard S, Sedgwick G, Lukas C, Hartmann-Petersen
R, Lukas J, Choudhary C, Pocock R, Bekker-Jensen S and Mailand N.
TITLE DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes
ubiquitin-dependent responses to replication blocks
JOURNAL Nat. Struct. Mol. Biol. 19 (11), 1084-1092 (2012)
PUBMED 23042605
REMARK GeneRIF: DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that
promotes ubiquitin-dependent responses to replication blocks.
REFERENCE 7 (residues 1 to 489)
AUTHORS Juhasz S, Balogh D, Hajdu I, Burkovics P, Villamil MA, Zhuang Z and
Haracska L.
TITLE Characterization of human Spartan/C1orf124, an ubiquitin-PCNA
interacting regulator of DNA damage tolerance
JOURNAL Nucleic Acids Res. 40 (21), 10795-10808 (2012)
PUBMED 22987070
REMARK GeneRIF: Authors propose that Spartan promotes genomic stability by
regulating the choice of rescue of stalled replication fork, whose
mechanism includes its interaction with ubiquitin-conjugated PCNA
and protection against PCNA deubiquitylation.
REFERENCE 8 (residues 1 to 489)
AUTHORS Ghosal G, Leung JW, Nair BC, Fong KW and Chen J.
TITLE Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124
is a regulator of translesion synthesis
JOURNAL J. Biol. Chem. 287 (41), 34225-34233 (2012)
PUBMED 22902628
REMARK GeneRIF: C1orf124 acts at multiple steps in TLS, stabilizes RAD18
and ubiquitinated PCNA at damage sites, and facilitates the switch
from replicative to TLS polymerase to bypass DNA lesion.
REFERENCE 9 (residues 1 to 489)
AUTHORS Machida Y, Kim MS and Machida YJ.
TITLE Spartan/C1orf124 is important to prevent UV-induced mutagenesis
JOURNAL Cell Cycle 11 (18), 3395-3402 (2012)
PUBMED 22894931
REMARK GeneRIF: Spartan is recruited to sites of stalled replication via
ubiquitinated PCNA and plays an important role to prevent mutations
associated with replication of damaged DNA.
REFERENCE 10 (residues 1 to 489)
AUTHORS Centore RC, Yazinski SA, Tse A and Zou L.
TITLE Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator
of UV-induced DNA damage response
JOURNAL Mol. Cell 46 (5), 625-635 (2012)
PUBMED 22681887
REMARK GeneRIF: Spartan promotes an unexpected feed-forward loop to
enhance PCNA ubiquitylation and translesion DNA synthesis.
COMMENT REVIEWED REFSEQ: This record has been curated by NCBI staff. The
reference sequence was derived from BC068478.1, AL117352.12 and
BU630543.1.
On Jan 29, 2005 this sequence version replaced NP_114407.2.
Summary: The protein encoded by this gene may play a role in DNA
repair during replication of damaged DNA. This protein recruits
valosin containing protein (p97) to stalled DNA replication forks
where it may prevent excessive translesional DNA synthesis and
limit the number of DNA-damage induced mutations. It may also be
involved in replication-related G2/M-checkpoint regulation.
Deficiency of a similar protein in mouse causes chromosomal
instability and progeroid phenotypes. Mutations in this gene have
been associated with Ruijs-Aalfs syndrome (RJALS). Alternatively
spliced transcript variants have been identified. [provided by
RefSeq, Mar 2015].
Transcript Variant: This variant (1) encodes the longest isoform
(A).
Sequence Note: This RefSeq record was created from transcript and
genomic sequence data to make the sequence consistent with the
reference genome assembly. The genomic coordinates used for the
transcript record were based on transcript alignments.
Publication Note: This RefSeq record includes a subset of the
publications that are available for this gene. Please see the Gene
record to access additional publications.
##Evidence-Data-START##
Transcript exon combination :: SRR1803615.161396.1,
SRR1803612.76500.1 [ECO:0000332]
RNAseq introns :: single sample supports all introns
SAMEA1965299, SAMEA1966682
[ECO:0000348]
##Evidence-Data-END##
##RefSeq-Attributes-START##
MANE Ensembl match :: ENST00000295050.12/ ENSP00000295050.7
RefSeq Select criteria :: based on conservation, expression,
longest protein
##RefSeq-Attributes-END##
FEATURES Location/Qualifiers
source 1..489
/organism="Homo sapiens"
/db_xref="taxon:9606"
/chromosome="1"
/map="1q42.2"
Protein 1..489
/product="sprT-like domain-containing protein Spartan
isoform a"
/note="zinc finger RAD18 domain-containing protein; DNA
damage-targeting VCP (p97) adaptor; DNA damage protein
targeting VCP"
/calculated_mol_wt=55003
Site 1
/site_type="acetylation"
/experiment="experimental evidence, no additional details
recorded"
/note="N-acetylmethionine. {ECO:0000244|PubMed:22814378};
propagated from UniProtKB/Swiss-Prot (Q9H040.2)"
Region 43..212
/region_name="SprT"
/note="SprT homologues; smart00731"
/db_xref="CDD:214794"
Region 253..261
/region_name="SHP-box"
/experiment="experimental evidence, no additional details
recorded"
/note="propagated from UniProtKB/Swiss-Prot (Q9H040.2)"
Site 268
/site_type="phosphorylation"
/experiment="experimental evidence, no additional details
recorded"
/note="Phosphoserine. {ECO:0000244|PubMed:23186163};
propagated from UniProtKB/Swiss-Prot (Q9H040.2)"
Region 325..332
/region_name="PIP-box"
/experiment="experimental evidence, no additional details
recorded"
/note="propagated from UniProtKB/Swiss-Prot (Q9H040.2)"
Region 453..476
/region_name="ZnF_Rad18"
/note="Rad18-like CCHC zinc finger; smart00734"
/db_xref="CDD:128973"
CDS 1..489
/gene="SPRTN"
/gene_synonym="C1orf124; DVC1; PRO4323; spartan"
/coded_by="NM_032018.7:92..1561"
/note="isoform a is encoded by transcript variant 1"
/db_xref="CCDS:CCDS1594.1"
/db_xref="GeneID:83932"
/db_xref="HGNC:HGNC:25356"
/db_xref="MIM:616086"
ORIGIN
1 mdddlmlalr lqeewnlqea erdhaqesls lvdaswelvd ptpdlqalfv qfndqffwgq
61 leavevkwsv rmtlcagics yegkggmcsi rlsepllklr prkdlvetll hemihaylfv
121 tnndkdregh gpefckhmhr insltganit vyhtfhdevd eyrrhwwrcn gpcqhrppyy
181 gyvkratnre psahdywwae hqktcggtyi kikepenysk kgkgkaklgk epvlaaenkd
241 kpnrgeaqlv ipfsgkgyvl getsnlpspg klitshaink tqdllnqnhs anavrpnski
301 kvkfeqngss knshlvspav snshqnvlsn yfprvsfanq kafrgvngsp risvtvgnip
361 knsvssssqr rvssskislr nsskvtesas vmpsqdvsgs edtfpnkrpr ledktvfdnf
421 fikkeqikss gndpkysttt aqnssssssq skmvncpvcq nevlesqine hldwclegds
481 ikvkseesl
//
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