8eza | pdb_00008eza

NHEJ Long-range complex with PAXX

Structural highlights

8eza is a 22 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	ATP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAXX_HUMAN Non-essential DNA repair protein involved in DNA non-homologous end joining (NHEJ); participates in double-strand break (DSB) repair and V(D)J recombination (PubMed:25574025, PubMed:25670504, PubMed:25941166, PubMed:27705800). May act as a scaffold required for accumulation of the Ku heterodimer, composed of XRCC5/Ku80 and XRCC6/Ku70, at double-strand break sites and promote the assembly and/or stability of the NHEJ machinery (PubMed:25574025, PubMed:25670504, PubMed:25941166). Involved in NHEJ by promoting the ligation of blunt-ended DNA ends (PubMed:27703001). Together with NHEJ1/XLF, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends (PubMed:30250067, PubMed:25670504). Constitutes a non-essential component of classical NHEJ: has a complementary but distinct function with NHEJ1/XLF in DNA repair (PubMed:27705800). Able to restrict infection by herpesvirus 1 (HSV-1) via an unknown mechanism (PubMed:29144403).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

DNA double-strand breaks (DSBs), one of the most cytotoxic forms of DNA damage, can be repaired by the tightly regulated nonhomologous end joining (NHEJ) machinery (Stinson and Loparo and Zhao et al.). Core NHEJ factors form an initial long-range (LR) synaptic complex that transitions into a DNA-PKcs (DNA-dependent protein kinase, catalytic subunit)-free, short-range state to align the DSB ends (Chen et al.). Using single-particle cryo-electron microscopy, we have visualized three additional key NHEJ complexes representing different transition states, with DNA-PKcs adopting distinct dimeric conformations within each of them. Upon DNA-PKcs autophosphorylation, the LR complex undergoes a substantial conformational change, with both Ku and DNA-PKcs rotating outward to promote DNA break exposure and DNA-PKcs dissociation. We also captured a dimeric state of catalytically inactive DNA-PKcs, which resembles structures of other PIKK (Phosphatidylinositol 3-kinase-related kinase) family kinases, revealing a model of the full regulatory cycle of DNA-PKcs during NHEJ.

Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ.,Chen S, Vogt A, Lee L, Naila T, McKeown R, Tomkinson AE, Lees-Miller SP, He Y Sci Adv. 2023 Jun 2;9(22):eadg2838. doi: 10.1126/sciadv.adg2838. Epub 2023 May , 31. PMID:37256947^[8]

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

References

↑ Ochi T, Blackford AN, Coates J, Jhujh S, Mehmood S, Tamura N, Travers J, Wu Q, Draviam VM, Robinson CV, Blundell TL, Jackson SP. DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science. 2015 Jan 9;347(6218):185-188. doi: 10.1126/science.1261971. PMID:25574025 doi:https://dx.doi.org/10.1126/science.1261971
↑ Xing M, Yang M, Huo W, Feng F, Wei L, Jiang W, Ning S, Yan Z, Li W, Wang Q, Hou M, Dong C, Guo R, Gao G, Ji J, Zha S, Lan L, Liang H, Xu D. Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway. Nat Commun. 2015 Feb 11;6:6233. doi: 10.1038/ncomms7233. PMID:25670504 doi:https://dx.doi.org/10.1038/ncomms7233
↑ Craxton A, Somers J, Munnur D, Jukes-Jones R, Cain K, Malewicz M. XLS (c9orf142) is a new component of mammalian DNA double-stranded break repair. Cell Death Differ. 2015 Jun;22(6):890-7. PMID:25941166 doi:10.1038/cdd.2015.22
↑ Chang HHY, Watanabe G, Gerodimos CA, Ochi T, Blundell TL, Jackson SP, Lieber MR. Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency. J Biol Chem. 2016 Nov 18;291(47):24377-24389. PMID:27703001 doi:10.1074/jbc.M116.752329
↑ Tadi SK, Tellier-Lebègue C, Nemoz C, Drevet P, Audebert S, Roy S, Meek K, Charbonnier JB, Modesti M. PAXX Is an Accessory c-NHEJ Factor that Associates with Ku70 and Has Overlapping Functions with XLF. Cell Rep. 2016 Oct 4;17(2):541-555. PMID:27705800 doi:10.1016/j.celrep.2016.09.026
↑ Trigg BJ, Lauer KB, Fernandes Dos Santos P, Coleman H, Balmus G, Mansur DS, Ferguson BJ. The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection. Viruses. 2017 Nov 16;9(11):342. PMID:29144403 doi:10.3390/v9110342
↑ Craxton A, Munnur D, Jukes-Jones R, Skalka G, Langlais C, Cain K, Malewicz M. PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair. Nat Commun. 2018 Sep 24;9(1):3877. PMID:30250067 doi:10.1038/s41467-018-06127-y
↑ Chen S, Vogt A, Lee L, Naila T, McKeown R, Tomkinson AE, Lees-Miller SP, He Y. Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ. Sci Adv. 2023 Jun 2;9(22):eadg2838. PMID:37256947 doi:10.1126/sciadv.adg2838

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Ochi T, Blackford AN, Coates J, Jhujh S, Mehmood S, Tamura N, Travers J, Wu Q, Draviam VM, Robinson CV, Blundell TL, Jackson SP. DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science. 2015 Jan 9;347(6218):185-188. doi: 10.1126/science.1261971. PMID:25574025 doi:https://dx.doi.org/10.1126/science.1261971

[2] Xing M, Yang M, Huo W, Feng F, Wei L, Jiang W, Ning S, Yan Z, Li W, Wang Q, Hou M, Dong C, Guo R, Gao G, Ji J, Zha S, Lan L, Liang H, Xu D. Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway. Nat Commun. 2015 Feb 11;6:6233. doi: 10.1038/ncomms7233. PMID:25670504 doi:https://dx.doi.org/10.1038/ncomms7233

[3] Craxton A, Somers J, Munnur D, Jukes-Jones R, Cain K, Malewicz M. XLS (c9orf142) is a new component of mammalian DNA double-stranded break repair. Cell Death Differ. 2015 Jun;22(6):890-7. PMID:25941166 doi:10.1038/cdd.2015.22

[4] Chang HHY, Watanabe G, Gerodimos CA, Ochi T, Blundell TL, Jackson SP, Lieber MR. Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency. J Biol Chem. 2016 Nov 18;291(47):24377-24389. PMID:27703001 doi:10.1074/jbc.M116.752329

[5] Tadi SK, Tellier-Lebègue C, Nemoz C, Drevet P, Audebert S, Roy S, Meek K, Charbonnier JB, Modesti M. PAXX Is an Accessory c-NHEJ Factor that Associates with Ku70 and Has Overlapping Functions with XLF. Cell Rep. 2016 Oct 4;17(2):541-555. PMID:27705800 doi:10.1016/j.celrep.2016.09.026

[6] Trigg BJ, Lauer KB, Fernandes Dos Santos P, Coleman H, Balmus G, Mansur DS, Ferguson BJ. The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection. Viruses. 2017 Nov 16;9(11):342. PMID:29144403 doi:10.3390/v9110342

[7] Craxton A, Munnur D, Jukes-Jones R, Skalka G, Langlais C, Cain K, Malewicz M. PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair. Nat Commun. 2018 Sep 24;9(1):3877. PMID:30250067 doi:10.1038/s41467-018-06127-y

[8] Chen S, Vogt A, Lee L, Naila T, McKeown R, Tomkinson AE, Lees-Miller SP, He Y. Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ. Sci Adv. 2023 Jun 2;9(22):eadg2838. PMID:37256947 doi:10.1126/sciadv.adg2838

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

8eza | pdb_00008eza

NHEJ Long-range complex with PAXX

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools