6t9q

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the second, C-terminal repeat of the DNA-binding domain of human TImeless

Structural highlights

6t9q is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6taz
Gene:	TIMELESS, TIM, TIM1, TIMELESS1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TIM_HUMAN] Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome, Timeless, harbours in its C-terminal region a previously unappreciated DNA-binding domain that exhibits specific binding to G-quadruplex (G4) DNA structures. We show that this domain contributes to maintaining processive replication through G4-forming sequences, and exhibits partial redundancy with an adjacent PARP-binding domain. Further, this function of Timeless requires interaction with and activity of the helicase DDX11. Loss of both Timeless and DDX11 causes epigenetic instability at G4-forming sequences and DNA damage. Our findings indicate that Timeless contributes to the ability of the replisome to sense replication-hindering G4 formation and ensures the prompt resolution of these structures by DDX11 to maintain processive DNA synthesis.

Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication.,Lerner LK, Holzer S, Kilkenny ML, Svikovic S, Murat P, Schiavone D, Eldridge CB, Bittleston A, Maman JD, Branzei D, Stott K, Pellegrini L, Sale JE EMBO J. 2020 Jul 23:e104185. doi: 10.15252/embj.2019104185. PMID:32705708^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gotter AL, Suppa C, Emanuel BS. Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol. 2007 Feb 9;366(1):36-52. Epub 2006 Nov 3. PMID:17141802 doi:http://dx.doi.org/S0022-2836(06)01525-7
↑ Unsal-Kacmaz K, Chastain PD, Qu PP, Minoo P, Cordeiro-Stone M, Sancar A, Kaufmann WK. The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol. 2007 Apr;27(8):3131-42. Epub 2007 Feb 12. PMID:17296725 doi:http://dx.doi.org/10.1128/MCB.02190-06
↑ Engelen E, Janssens RC, Yagita K, Smits VA, van der Horst GT, Tamanini F. Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PLoS One. 2013;8(2):e56623. doi: 10.1371/journal.pone.0056623. Epub 2013 Feb 13. PMID:23418588 doi:http://dx.doi.org/10.1371/journal.pone.0056623
↑ Sangoram AM, Saez L, Antoch MP, Gekakis N, Staknis D, Whiteley A, Fruechte EM, Vitaterna MH, Shimomura K, King DP, Young MW, Weitz CJ, Takahashi JS. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron. 1998 Nov;21(5):1101-13. PMID:9856465
↑ Lerner LK, Holzer S, Kilkenny ML, Svikovic S, Murat P, Schiavone D, Eldridge CB, Bittleston A, Maman JD, Branzei D, Stott K, Pellegrini L, Sale JE. Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication. EMBO J. 2020 Jul 23:e104185. doi: 10.15252/embj.2019104185. PMID:32705708 doi:http://dx.doi.org/10.15252/embj.2019104185

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6t9q"

@@ Line 3: / Line 3: @@
 <StructureSection load='6t9q' size='340' side='right'caption='[[6t9q]], [[Resolution|resolution]] 1.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6t9q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T9Q OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T9Q FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6t9q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T9Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T9Q FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6taz|6taz]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TIMELESS, TIM, TIM1, TIMELESS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TIMELESS, TIM, TIM1, TIMELESS1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6t9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t9q OCA], [http://pdbe.org/6t9q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t9q RCSB], [http://www.ebi.ac.uk/pdbsum/6t9q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t9q ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6t9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t9q OCA], [https://pdbe.org/6t9q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t9q RCSB], [https://www.ebi.ac.uk/pdbsum/6t9q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t9q ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/TIM_HUMAN TIM_HUMAN]] Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.<ref>PMID:17141802</ref> <ref>PMID:17296725</ref> <ref>PMID:23418588</ref> <ref>PMID:9856465</ref>
+[[https://www.uniprot.org/uniprot/TIM_HUMAN TIM_HUMAN]] Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.<ref>PMID:17141802</ref> <ref>PMID:17296725</ref> <ref>PMID:23418588</ref> <ref>PMID:9856465</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

6t9q

From Proteopedia

Current revision

Crystal structure of the second, C-terminal repeat of the DNA-binding domain of human TImeless

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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