Abstract
Nucleotide excision repair removes DNA lesions caused by ultraviolet light, cisplatin-like compounds and bulky adducts1. After initial recognition by XPC in global genome repair or a stalled RNA polymerase in transcription-coupled repair, damaged DNA is transferred to the seven-subunit TFIIH core complex (Core7) for verification and dual incisions by the XPF and XPG nucleases2. Structures capturing lesion recognition by the yeast XPC homologue Rad4 and TFIIH in transcription initiation or DNA repair have been separately reported3,4,5,6,7. How two different lesion recognition pathways converge and how the XPB and XPD helicases of Core7 move the DNA lesion for verification are unclear. Here we report on structures revealing DNA lesion recognition by human XPC and DNA lesion hand-off from XPC to Core7 and XPA. XPA, which binds between XPB and XPD, kinks the DNA duplex and shifts XPC and the DNA lesion by nearly a helical turn relative to Core7. The DNA lesion is thus positioned outside of Core7, as would occur with RNA polymerase. XPB and XPD, which track the lesion-containing strand but translocate DNA in opposite directions, push and pull the lesion-containing strand into XPD for verification.
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Data availability
The structures and cryo-EM maps have been deposited with the PDB and the EMDB, respectively, under the accession codes 8EBS, 8EBT and 8EBU, and EMD-27996, EMD-27997 and EMD-27998 for C7CD, C7CAD and C7AD of Cy5; 8EBV, 8EBW, 8EBX and 8EBY, and EMD-27999, EMD-28000, EMD-28001 and EMD-28002 for C7CD1, C7CD2, C7CAD and C7AD of AP. The focused refinement maps of XPC–lesion DNA in Cy5_C7CD and the C-terminal domain of XPC in C7CAD and C7AD have been deposited with the EMDB under the accession codes EMD-29674 and EMD-29673, respectively. Other research materials reported here are available on request.
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Acknowledgements
The authors thank R. Craigie, M. Gellert, H. Lans, D. Leahy and W. Vermeulen for critical reading of the manuscript, and J. Li for preparing carbon-filmed cryo-EM grids. This work utilized the Cryo-Electron Microscopy Core facility, the NIDDK and the NIH Multi-Institute Cryo-EM Facility (MICEF). This research was supported by the NIDDK (DK075037) to W.Y. and Grants-in-Aid (KAKENHI) (grant numbers JP16H06307 and JP21H03598) to K.S.
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J.K. carried out the biochemical and structural studies. C.-L.L. carried out the dual-incision assays. F.M.G. developed the GraFix protocol. H.W. and Y.C. helped with the cryo-EM grid preparation and data acquisition. Y.C. and X.C. helped with the cryo-EM data processing and map improvement. K.S. and W.Y. conceived the research project. W.Y. supervised experimental design and data interpretation. K.S. and F.H. helped with data interpretation. All authors were involved in writing the paper and adhere to the ‘inclusion and ethics’ regulation.
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Extended data figures and tables
Extended Data Fig. 1 Structures of NER complexes.
(a) Yeast Rad4 (XPC) complexed with Core7 and damaged DNA (orange and yellow) (PDB: 7K04 at 9.25 Å). (b) Human XPA and Core7 are complexed with undamaged but branched DNA (PDB: 6RO4). These structures are superimposed at XPB. The DNA damage site is far away and upstream of the lesion sensor Fe4S4 (marked by the grey arrowheads). (c) For comparison, the structures reported here, human XPC and Core7 complex with Cy5-DNA (C7CD), is shown after superposition with 7K04. (d) In human XPC, XPA and Core7 complexed with Cy5-DNA (C7CAD), the DNA lesion (Cy5) is downstream of the XPD motor (5′ to 3′) and close to the lesion sensor Fe4S4 of XPD. when XPD translocates along the lesion strand (orange), Cy5 would be “seen” and stall the XPD motor.
Extended Data Fig. 2 Structure determination of three Cy5 structures.
(a) Diagram of Cy5-DNA and Cy5. (b) The workflow of cryoEM data processing and model generation. (c) FSC analysis of the quality and map resolution and model fit of each complex structure. (d) For each complex, angular distributions of particles used for the final three-dimensional reconstruction, and a surface presentation of its map colored according to the local resolution estimated by ResMap with the scale bar on the side, are shown. (e) Representative regions of the three cryoEM maps are superimposed with the final structural models.
Extended Data Fig. 3 Structure determination of four AP structures.
(a) Diagram of the AP-DNA, and EMSA results of 5 nM 32P-labeled AP-DNA binding by 5 nM each of XPA, Core7, Core7 and XPA (C7A), XPC, XPC and XPA (CA), Core7 and XPC (C7C) and Core7 with XPC and XPA (C7CA). The EMSA results were replicated at least six times. (b) The workflow of cryoEM data processing and model generation. (c) FSC analysis of the quality and map resolution and model fit of each complex structure. (d) For each complex, angular distributions of particles used for the final three-dimensional reconstruction, and a surface presentation of its map, colored according to the local resolution estimated by ResMap with the scale bar on the side, are shown. (e) Representative regions of the three cryoEM maps (DNA) are superimposed with the final structural models. For gel source data of a, see Supplementary Fig. 3.
Extended Data Fig. 4 Structure-based sequence alignment of human XPC and yeast Rad4.
Conserved residues are highlighted in yellow (hydrophobic core), grey (structural stability), green (subunit interface), cyan (DNA binding, and underscore indicating base interactions), and red (disease mutation). Protein secondary structures are indicated by box (for helix) and arrow (strand). They are labeled alphabetically for helices and numerically for strands. In BHD domains 1-3, secondary structures are preceded by domain name “1”, “2” and “3”. Disordered regions are indicated by dashed lines.
Extended Data Fig. 5 cryoEM maps of DNA bound by XPC and XPA.
(a) The flipped out T26 in Cy5_C7CD. (b) The LHN has close contacts with Cy5 and the non-lesion strand across the minor groove. The cryoEM map in the above two panels are shown as semi-transparency grey surface. (c) cryoEM map corresponding to XPA and DNA in Cy5_C7CAD. Map volume is color coded and labeled. (d) A close-up of the C-terminal 52 residues of XPC (aa 889-940). XPB, p52, and p8 of Core7 and XPC are represented by the cryoEM map of C7CAD and C7AD of Cy5-DNA and color coded. Helices L, M and N of XPC are show as ribbon cartoons and labeled. The penultimate K939 of XPC, which is shown in a stick model, caps the carboxyl end of helix N. Potential interactions between the sidechain amine of K939 (shown as a sphere) and carbonyl oxygens are indicated by dashed yellow lines. Residues F935, P936 and F937 of XPC are anchored in a hydrophobic pocket in XPB (green).
Extended Data Fig. 6 Domain comparison of XPC, Rad4, RAD23 and CETN2.
(a) Superposition of TGD of XPC (slate blue) and Rad4 (semi-transparent grey). (b) Superposition of BHD1 of XPC and Rad4. (c) Superposition of BHD2 of XPC and Rad4. (d) Superposition of BHD3 of XPC and Rad4. (e) Superposition of Rad23 and RAD23 (pale green cartoon with molecular surface) reveals that TGD domains of XPC (blue) and Rad4 (grey) differ by a 16° rotation. (f) Superposition of TGD domains of XPC and Rad4 reveals that BHD1, BHD2 and BHD3 diverge increasingly. (g) Crystal structures of CETN2 (2GGM in pink and 2OBH in light blue) complexed with XPC peptide (LHC, blue) are superimposed. Symmetry mate of XPC is shown in pale green. (h) CETN2 (light green) and XPB (dark green) in C7CD are included in superposition. The LHC (XPC, dark blue) is shifted and interacts with the C-terminal helix of XPB when complexed with Core7.
Extended Data Fig. 7 Structure comparison of C7CD with PIC and XPB with SF2 helicase.
(a) Superposition of XPB (green) in C7CD and in human PIC (PDB: 7NVW, light grey) shows the bent DNA associated with XPB and different position of XPD (cyan in C7CD and light grey in PIC) in the U-shaped Core7. (b) Superposition of HD2 of four SF helicases, XPB, Rad26 (CSB homolog), Snf2 and NS3 reveals that the tracking strands superimpose well in all cases.
Extended Data Fig. 8 Repetitive and flexible structure of TFIIH (Core7).
(a) The U-shaped Core7 in C7CD. The N-terminal helices of p44 that contact XPB are outlined in a rounded rectangle. The XPD (left) and XPB (right) arm are well separated. (b) The σ-shaped Core7 in C7CAD with p34 superimposed to C7CD and viewed in the same orientation as in panel a. The interface at p34-p44 and p34-p52 (inside the dashed oval) remain unchanged. (c) The stable interfaces of p34 with p44-RING finger (RF) and p52. The C-terminal p34-DZF (double Zinc finger) and p44-ZR (Zing Ribbon) domain are labeled. (d) A β hairpin of p34-DZF in C7CD is changed to a short α helix in C7CAD. A part of p62 becomes disordered in C7CAD. (e) The third domain of p52 (DRD fold) contacts the N-terminal DRD domain (blueish) of XPB, which is followed by the second DRD domain (greenish) of XPB. The N-terminal helices of p44 (pink) contact the back side of XPB. (f) The fourth domain of p52 (grey) and p8 (light purple) form a heterodimer.
Extended Data Fig. 9 Comparison of DRD (Damage Recognition Domain) domains.
Two MutS DRDs (domains I and VI from 1EWQ) are shown on the left side for comparison. Five DRD domains in TFIIH are shown after superposition with MutS DRDs. Each DRD is colored in rainbow fashion from the blue N- to red C-terminus. Four β strands are labeled 1 to 4, and strands 2 and 4 are each followed by an α helix (A and B). In the P52-p8 heterodimer, the two subunits complement each other by supply the partner DRD with the first β strand (shown in semi-transparent blue and labeled 1′).
Extended Data Fig. 10 Length of Cy5_DNA substrate required for efficient dual incision.
(a) Sequence of three Cy5 DNA substrates, each of which contains a total 94 bp but different upstream (left) and downstream length from Cy5 (right). (b) Diagrams of the three DNA substrates. (c) Dual incision results of each DNA substrate (sub) after incubation with Core7, XPC, XPA, RPA, XPF and XPG at 37 °C for 60 min. DNA cleavage intermediate (int) and final product (prod) are marked. (d) Means and standard deviations (error bars) of triplicated dual incision reactions as well as individual data points are shown in the bar graph. For gel source data, see Supplementary Fig. 5.
Supplementary information
Supplementary Information
This file contains Supplementary Table 1 and Supplementary Figs. 1–5.
Supplementary Video 1
Movement of XPC between flipping out 3 and 2 nt. The movie was generated based on Cy5_C7CD and AP_C7CD (conf2). Protein subunits are color-coded according to Fig. 1a. The trimeric XPC translocates downstream of the lesion by 1 bp, which involves ~36° rotation and ~3.4 Å translation.
Supplementary Video 2
Movement of Core7 relative to XPC-DNA upon XPA binding. The movie was generated based on Cy5_C7CD (C7CD) and Cy5_C7CAD. The attachment of the C-terminus of XPC to Core7 (XPB-p52-p8) prevents Core7 and XPC from dissociation. XPA is included in the last frame.
Supplementary Video 3
Structural changes between Cy5_C7CAD and AP_C7CAD. AP-DNA is more bent at the lesion site than Cy5, but it is more relaxed (straight) upstream of the lesion, where XPB and XPA bind.
Supplementary Video 4
Conformational changes from the U-shaped Core7 in C7CD to the σ shape in C7CAD. The XPB and XPD arms move relatively to the unchanged p52-p34-p44 interface at the U-turn.
Supplementary Video 5
An orthogonal view of the XPB and XPD movement between C7CD and C7CAD. This viewpoint shows the crossing of XPB and XPD subunits when forming the closed σ shape in C7CAD.
Supplementary Video 6
Movement of the XPD arm from C7CD to C7CAD. The flexible joint formed by p34-p44 in the XPD arm is stabilized by the p62 helical bundle.
Supplementary Video 7
Movement of the XPB arm from C7CD to C7CAD. The extensive domain interface between p52 and XPB allows XPB to undergo precession-like movement.
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Kim, J., Li, CL., Chen, X. et al. Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. Nature 617, 170–175 (2023). https://doi.org/10.1038/s41586-023-05959-z
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DOI: https://doi.org/10.1038/s41586-023-05959-z
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