7lsy

From Proteopedia

(Difference between revisions)

Current revision

NHEJ Short-range synaptic complex

Structural highlights

7lsy is a 17 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 8.4Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

XRCC6_HUMAN Single stranded DNA-dependent ATP-dependent helicase. Has a role in chromosome translocation. The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner. It works in the 3'-5' direction. Binding to DNA may be mediated by XRCC6. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The XRCC5/6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. The XRCC5/6 dimer is probably involved in stabilizing broken DNA ends and bringing them together. The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step. Required for osteocalcin gene expression. Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site near double-strand breaks. 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined. The XRCC5/6 dimer together with APEX1 acts as a negative regulator of transcription.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis(1,2). The conserved error-prone non-homologous end joining (NHEJ) pathway has a key role in determining the effects of DSB-inducing agents that are used to treat cancer as well as the generation of the diversity in antibodies and T cell receptors(2,3). Here we applied single-particle cryo-electron microscopy to visualize two key DNA-protein complexes that are formed by human NHEJ factors. The Ku70/80 heterodimer (Ku), the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), DNA ligase IV (LigIV), XRCC4 and XLF form a long-range synaptic complex, in which the DNA ends are held approximately 115 A apart. Two DNA end-bound subcomplexes comprising Ku and DNA-PKcs are linked by interactions between the DNA-PKcs subunits and a scaffold comprising LigIV, XRCC4, XLF, XRCC4 and LigIV. The relative orientation of the DNA-PKcs molecules suggests a mechanism for autophosphorylation in trans, which leads to the dissociation of DNA-PKcs and the transition into the short-range synaptic complex. Within this complex, the Ku-bound DNA ends are aligned for processing and ligation by the XLF-anchored scaffold, and a single catalytic domain of LigIV is stably associated with a nick between the two Ku molecules, which suggests that the joining of both strands of a DSB involves both LigIV molecules.

Structural basis of long-range to short-range synaptic transition in NHEJ.,Chen S, Lee L, Naila T, Fishbain S, Wang A, Tomkinson AE, Lees-Miller SP, He Y Nature. 2021 May;593(7858):294-298. doi: 10.1038/s41586-021-03458-7. Epub 2021 , Apr 14. PMID:33854234^[8]

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

References

↑ Reeves WH, Sthoeger ZM. Molecular cloning of cDNA encoding the p70 (Ku) lupus autoantigen. J Biol Chem. 1989 Mar 25;264(9):5047-52. PMID:2466842
↑ Chung U, Igarashi T, Nishishita T, Iwanari H, Iwamatsu A, Suwa A, Mimori T, Hata K, Ebisu S, Ogata E, Fujita T, Okazaki T. The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium. J Biol Chem. 1996 Apr 12;271(15):8593-8. PMID:8621488
↑ Tuteja N, Tuteja R, Ochem A, Taneja P, Huang NW, Simoncsits A, Susic S, Rahman K, Marusic L, Chen J, et al.. Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen. EMBO J. 1994 Oct 17;13(20):4991-5001. PMID:7957065
↑ West RB, Yaneva M, Lieber MR. Productive and nonproductive complexes of Ku and DNA-dependent protein kinase at DNA termini. Mol Cell Biol. 1998 Oct;18(10):5908-20. PMID:9742108
↑ Willis DM, Loewy AP, Charlton-Kachigian N, Shao JS, Ornitz DM, Towler DA. Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex. J Biol Chem. 2002 Oct 4;277(40):37280-91. Epub 2002 Jul 26. PMID:12145306 doi:http://dx.doi.org/10.1074/jbc.M206482200
↑ Liu H, Herrmann CH, Chiang K, Sung TL, Moon SH, Donehower LA, Rice AP. 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem Biophys Res Commun. 2010 Jun 25;397(2):245-50. doi:, 10.1016/j.bbrc.2010.05.092. Epub 2010 May 20. PMID:20493174 doi:10.1016/j.bbrc.2010.05.092
↑ Roberts SA, Strande N, Burkhalter MD, Strom C, Havener JM, Hasty P, Ramsden DA. Ku is a 5'-dRP/AP lyase that excises nucleotide damage near broken ends. Nature. 2010 Apr 22;464(7292):1214-7. doi: 10.1038/nature08926. Epub 2010 Apr 11. PMID:20383123 doi:http://dx.doi.org/10.1038/nature08926
↑ Chen S, Lee L, Naila T, Fishbain S, Wang A, Tomkinson AE, Lees-Miller SP, He Y. Structural basis of long-range to short-range synaptic transition in NHEJ. Nature. 2021 May;593(7858):294-298. PMID:33854234 doi:10.1038/s41586-021-03458-7

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lsy"

Categories: Homo sapiens | Large Structures | Chen S | He Y

@@ Line 1: / Line 1: @@
-====
+==NHEJ Short-range synaptic complex==
-<StructureSection load='7lsy' size='340' side='right'caption='[[7lsy]]' scene=''>
+<StructureSection load='7lsy' size='340' side='right'caption='[[7lsy]], [[Resolution|resolution]] 8.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7lsy]] is a 17 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LSY FirstGlance]. <br>
-</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=7lsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lsy OCA], [https://pdbe.org/7lsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lsy RCSB], [https://www.ebi.ac.uk/pdbsum/7lsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lsy ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 8.4&#8491;</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=7lsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lsy OCA], [https://pdbe.org/7lsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lsy RCSB], [https://www.ebi.ac.uk/pdbsum/7lsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lsy ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/XRCC6_HUMAN XRCC6_HUMAN] Single stranded DNA-dependent ATP-dependent helicase. Has a role in chromosome translocation. The DNA helicase II complex binds preferentially to fork-like ends of double-stranded DNA in a cell cycle-dependent manner. It works in the 3'-5' direction. Binding to DNA may be mediated by XRCC6. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The XRCC5/6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. The XRCC5/6 dimer is probably involved in stabilizing broken DNA ends and bringing them together. The assembly of the DNA-PK complex to DNA ends is required for the NHEJ ligation step. Required for osteocalcin gene expression. Probably also acts as a 5'-deoxyribose-5-phosphate lyase (5'-dRP lyase), by catalyzing the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site near double-strand breaks. 5'-dRP lyase activity allows to 'clean' the termini of abasic sites, a class of nucleotide damage commonly associated with strand breaks, before such broken ends can be joined. The XRCC5/6 dimer together with APEX1 acts as a negative regulator of transcription.<ref>PMID:2466842</ref> <ref>PMID:8621488</ref> <ref>PMID:7957065</ref> <ref>PMID:9742108</ref> <ref>PMID:12145306</ref> <ref>PMID:20493174</ref> <ref>PMID:20383123</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis(1,2). The conserved error-prone non-homologous end joining (NHEJ) pathway has a key role in determining the effects of DSB-inducing agents that are used to treat cancer as well as the generation of the diversity in antibodies and T cell receptors(2,3). Here we applied single-particle cryo-electron microscopy to visualize two key DNA-protein complexes that are formed by human NHEJ factors. The Ku70/80 heterodimer (Ku), the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), DNA ligase IV (LigIV), XRCC4 and XLF form a long-range synaptic complex, in which the DNA ends are held approximately 115 A apart. Two DNA end-bound subcomplexes comprising Ku and DNA-PKcs are linked by interactions between the DNA-PKcs subunits and a scaffold comprising LigIV, XRCC4, XLF, XRCC4 and LigIV. The relative orientation of the DNA-PKcs molecules suggests a mechanism for autophosphorylation in trans, which leads to the dissociation of DNA-PKcs and the transition into the short-range synaptic complex. Within this complex, the Ku-bound DNA ends are aligned for processing and ligation by the XLF-anchored scaffold, and a single catalytic domain of LigIV is stably associated with a nick between the two Ku molecules, which suggests that the joining of both strands of a DSB involves both LigIV molecules.
+Structural basis of long-range to short-range synaptic transition in NHEJ.,Chen S, Lee L, Naila T, Fishbain S, Wang A, Tomkinson AE, Lees-Miller SP, He Y Nature. 2021 May;593(7858):294-298. doi: 10.1038/s41586-021-03458-7. Epub 2021 , Apr 14. PMID:33854234<ref>PMID:33854234</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7lsy" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[DNA ligase 3D structures|DNA ligase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Z-disk]]
+[[Category: Chen S]]
+[[Category: He Y]]

7lsy

From Proteopedia

Current revision

NHEJ Short-range synaptic complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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