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Repriming of DNA synthesis at stalled replication forks by human PrimPol

Nature Structural & Molecular Biology volume 20, pages 1383–1389 (2013)Cite this article

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Abstract

DNA replication forks that collapse during the process of genomic duplication lead to double-strand breaks and constitute a threat to genomic stability. The risk of fork collapse is higher in the presence of replication inhibitors or after UV irradiation, which introduces specific modifications in the structure of DNA. In these cases, fork progression may be facilitated by error-prone translesion synthesis (TLS) DNA polymerases. Alternatively, the replisome may skip the damaged DNA, leaving an unreplicated gap to be repaired after replication. This mechanism strictly requires a priming event downstream of the lesion. Here we show that PrimPol, a new human primase and TLS polymerase, uses its primase activity to mediate uninterrupted fork progression after UV irradiation and to reinitiate DNA synthesis after dNTP depletion. As an enzyme involved in tolerance to DNA damage, PrimPol might become a target for cancer therapy.

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Figure 1: PrimPol associates with nuclear chromatin in unperturbed S phase and in response to DNA damage.
Figure 2: Loss of PrimPol causes slow proliferation, replicative stress and genomic instability.
Figure 3: Slow fork progression after PrimPol downregulation.
Figure 4: Inefficient restart of stalled forks and activation of dormant origins upon UV irradiation.
Figure 5: PrimPol TLS synthesis capacity on CPD and (6-4)pp lesions is not sufficient to mediate restart of replication forks.
Figure 6: PrimPol acts independently of Polη to promote fork progression through DNA damaged by UV irradiation.

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Acknowledgements

We thank all members of our laboratories for helpful discussions, S. Iwai (Osaka University) for the (6-4)pp oligonucleotide, Z.F. Pursell (Tulane University School of Medicine) for purified Polɛ, J.-S. Hoffmann (Cancer Research Center of Toulouse, France) for anti-Polη, M. Soengas (Spanish National Cancer Research Centre) for HDF cells, P. Delgado for assistance with lymphocyte isolation, M. Pérez and D. Megías for assistance with confocal microscopy and life cell imaging, M.F. Rodríguez-Tornos for her contribution to the early stages of this project, B. Urcelay for technical support in J.M.'s lab, and M. Serrano and A.R. Ramiro for helpful comments on the manuscript. This work was supported by Comunidad de Madrid (S2011/BMD-2361 to L.B.) and the Spanish Ministry of Economy and Competitiveness (BFU2010-21467 to J.M., BFU2012-37969 to L.B., Consolider CSD2007-00015 to L.B. and J.M.).

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Author notes

  1. Sara Rodriguez-Acebes and María I Martínez-Jiménez: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Oncology Program, Spanish National Cancer Research Centre, Madrid, Spain

    Silvana Mourón, Sara Rodriguez-Acebes & Juan Méndez

  2. Department of Genome Dynamics and Function, Centro de Biología Molecular “Severo Ochoa”, Madrid, Spain

    María I Martínez-Jiménez, Sara García-Gómez, Sandra Chocrón & Luis Blanco

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  1. Silvana Mourón
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Contributions

S.M. and S.R.-A. performed experiments in the cellular system, including single-molecule analysis of DNA replication in stretched fibers. M.I.M.-J. and S.G.-G. performed in vitro assays relative to PrimPol biochemical activities. S.C. isolated Primpol−/− MEFs. L.B. and J.M. designed the study and led data analysis and interpretation, with contributions from all other authors. J.M. wrote the manuscript.

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Correspondence to Luis Blanco or Juan Méndez.

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Integrated supplementary information

Supplementary Figure 1 PrimPol mRNA and protein levels in the cell cycle. Chromatin association in response to DNA damage.

(a) Left panel: quantification of PrimPol mRNA levels by RT-PCR in cells synchronized at the indicated cell cycle stages. A, asynchronous cell culture. Right panel: PrimPol total protein levels, detected by immunoblot in the same cell populations. Mek2 serves as loading control. DNA content profile for each population is shown. (b) Histograms showing the ratio of chromatin-associated vs. soluble PrimPol protein in HeLa and U2OS cells exposed to the indicated treatment (Materials and Methods) and quantified from immunoblot signals such as those shown in main Figure 1b. In each case, chromatin/soluble PrimPol ratios are expressed as fold-change relative to the ratio obtained in untreated cells. (c) Immunoblots showing the distribution of PrimPol in soluble (S) vs. chromatin-bound (C) fractions in HeLa cells in the absence (lanes 1–6) or presence (lanes 7–12) of 2 mM HU. When indicated, cells were treated with 7.5 mM caffeine or 0.4 mM UCN01. Mek2 and CTCF are shown as controls of the soluble and chromatin fractions, respectively. (d) Recruitment of GFP-PrimPol to sites of laser-induced DNA damage in U2OS cell nuclei (depicted as dashed yellow lines in the leftmost images). Time lapsed between laser irradiation and image acquisition is indicated in minutes. GFP-53BP1 and GFP-H2AB were used as positive and negative control, respectively. Scale bar, 10 μm. Data are pooled from 3 experiments (left panel) and representative of 3 experiments (right panel) (a), pooled from 3 experiments for each cell line (b), representative of 3 experiments (c), representative of 16 laser-responsive cells from a total of 54 irradiated cells (PrimPol), 16 laser-responsive cells from a total of 35 irradiated cells (53BP1), 12 irradiated cells (H2AB) (d). Error bars, s.d. (a,b).

Supplementary Figure 2 Slow cell proliferation and signs of chromosomal instability after PrimPol downregulation.

(a) Cell proliferation profiles of U2OS-shPrimPol with or without Dox. The efficiency of PrimPol downregulation at each time point is shown in immunoblots, with Mek2 as loading control. (b) Distribution of HeLa-shPrimPol cells in the different phases of the cell cycle, after 72 h in the absence or presence of Dox. Percentages of cells in each phase were calculated from DNA content profiles generated by flow cytometry after propidium iodide staining. (c) Flow cytometry detection of BrdU incorporation after a 30 min pulse with 10 μM BrdU in HeLa-shPrimPol with or without Dox. The histogram represents percentage of BrdU-positive cells. (d) Left: representative images of aberrant mitotic figures in HeLa-shPrimPol cells. Arrows mark the position of misaligned chromosomes in metaphase and lagging chromosomes in anaphase. Microtubules were stained with anti-α-tubulin (green) and anti-γ-tubulin (red). DNA was stained with DAPI (gray). Scale bar, 5 μm. Bar graphs indicate the percentage of abnormal metaphases or anaphases in the absence or presence of Dox. (e) Similar analysis as in (d), carried out in WT or PrimPol KO MEFs. (f) Representative images of chromosomal breaks and gaps in metaphase spreads of T lymphocytes derived from PrimPol KO mice. (g) Left, representative images of triradial and tetraradial chromosomal fusions in metaphase spreads of T lymphocytes derived from PrimPol KO mice. Histogram (right) shows the percentage of metaphases showing chromosome fusions in each case. Immunoblots are representative of 3 experiments that were pooled for growth curves (a), data are pooled from 5 experiments (b), flow cytometry plots are representative of 5 experiments, which are pooled in the histograms (c), images are representative of 4 experiments, combined in the histograms (d), data are pooled from 3 experiments (e), images are representative from the analysis of 80 metaphases per condition (2 mice per genotype) (f,g). Error bars, s.d. (b–e, g), *P<0.05, ***P<0.001. (Student's t-test) (d,e).

Supplementary Figure 3 Defective fork progression, inefficient fork restart and dormant origin activation upon PrimPol downregulation.

(a) Immunoblots showing the downregulation of endogenous PrimPol in HeLa-shPrimPol cells upon addition of Dox (lanes 1–2) and the efficient expression of the exogenous versions of the enzyme, detected with anti-PrimPol and anti-V5 (lanes 3–6). The asterisk marks a species cross-reacting with the anti-V5 antibody. Mek2 is shown as loading control. (b) Schematic of the labeling assay in which the CldU and IdU pulses are separated by a 5h HU treatment. Bottom, flow cytometry profiles of BrdU incorporation in asynchronous (Asy) or HU-treated cells. (c) Left panel: Histograms showing the percentage of fork restart after HU treatment in HeLa-shPrimPol cells with or without Dox. When indicated, plasmids expressing V5-tagged PrimPol (either WT or AxA mutant) were transfected. Right panel: Percentage of fork restart after HU in MEFs derived from WT or PrimPol KO mice. (d) Immunoblots comparing PrimPol levels in HDF-shPrimPol cells incubated with or without Dox for 72 h (lanes 4 and 5). Lanes 1–3 show serial dilutions (12.5, 25, 50%) of the sample analyzed in lane 4, for quantification purposes. (e,f) Scatter plots showing FR (e) or IOD (f) values in HDF-shPrimPol with or without Dox. (g) Percentage of fork rescue after UV irradiation (30 J/m2) in HDF-shPrimPol cells with or without Dox. Data are representative of 3 experiments (a,b), pooled from 2 (HeLa-shPrimPol) or 3 experiments (MEFs) (c), representative of 2 experiments (d), pooled from 2 experiments (e–g). Error bars, s.d. **P<0.01, ***P<0.001 (Student's t-test), NS, not significative (c,g). Horizontal lines represent median, ***P<0.001 (Mann-Whitney test) (e,f).

Supplementary Figure 4 Human Polɛ is not able to proceed through CPD Thy adducts and (6-4)pp lesions.

(a) Left, primer extension assay using purified human Pole on a control template. The full extension product is 27 nucleotides longer than the original primer. Right, primer extension assay using a CPD-containing template. The position of the CPD (T=T) is indicated in red. Polɛ could only extend the primer by 3 nucleotides (TAT, shown in blue) before stopping at the lesion. dNTP concentrations used: 1, 5, 10 μM. (b) Left, primer extension assay using another control template in which the full extension product is 17 nucleotides longer than the original primer. Right, similar assay using a (6-4)pp-containing template. The position of the (6-4)pp is indicated in red. As in (a), Polɛ was unable to bypass the lesion, extending the primer by only 3 nucleotides (ATG, shown in blue). dNTP concentrations used: 1, 5, 10 μM. Data are representative of 4 experiments (a,b).

Supplementary Figure 5 PrimPol realigns the primer-terminus ahead of the (6-4)pp lesion.

(a) TLS assay with a primer which hybridizes immediately before the (6-4)pp lesion (standing start). In an undamaged template, PrimPol elongated this primer until the expected +14 product (left panel; dNTPs: 1, 10 μM). In contrast, full length product was very scarce when copying the (6-4)pp-containing template (right panel). Instead, a main band was obtained corresponding to a +8 product, and a minor +11 band was also noticeable. (b) Standing start extension in the presence of the indicated dNTPs (10 μM), showing that dCTP is required for efficient primer extension in the (6-4)pp template. (c) Analysis of the first (+1) dNTP added to the primer in standing-start conditions. In the control template (left), dATP is the preferred nucleotide, whereas in the lesion-containing template (right), dCTP is preferentially inserted, with dA, dG and dT as secondary options. The bands corresponding to the primer (P) and elongation products (+1, +2, etc) are indicated. (d) Correlative insertion of dC, dT and dG, each provided at 1 mM, at control (left) and (6-4)pp-containing (right) templates. (e) Schematics summarizing the origin and relative abundance of the different products observed in (a) and (b). Direct extension allows the efficient copy of the normal template (+14); conversely, the small amount of the +14 product reflects inefficient synthesis opposite the (6-4)pp lesion. The (6-4)pp lesion (and the corresponding two Ts in the control template) is flanked by a 4 nt microhomology region (highlighted in yellow) that provides an opportunity to realign the primer-terminus as an alternative to copying the damaged bases (realignment beyond the lesion), explaining the most abundant +8 product on the (6-4)pp-containing template and the initial synthesis of CTG shown in (d). The same realignment could also take place in the control template, but is outcompeted by direct extension of the primer. Data are representative of 5 experiments (a), 3 experiments (b,c), 2 experiments (d).

Supplementary Figure 6 Human PrimPol variants affecting the Zn finger are capable of lesion bypass, but are unable of rescuing fork restart upon HU.

(a) Schematic of human PrimPol, outlining the three motifs (A,B,C) forming the AEP active site, and the more specific C-terminal Zn-finger motif (Z). The two PrimPol variants generated in this work are ΔZn (1-409), lacking the C-terminal 151 aa, and CH (C419G/H426Y), a double point mutant at the Zn-finger motif. A multiple amino acid sequence alignment of different PrimPol orthologues from Eukarya (animals and plants) is shown, encompassing the C-terminal region containing the putative Zn-finger. The Cys and His forming the conserved motif Cx6H—x19—Cx4C, that likely coordinate the Zn atom, are marked with cyan dots above the human sequence. (b) Zn-finger PrimPol mutants (ΔZn and CH) are capable of lesion bypass in templates containing CPD (left) and (6-4)pp (right) photoproducts. (c) Bar graphs showing the percentage of fork rescue upon HU treatment in HeLa-shPrimPol cells with or without Dox. When indicated, plasmids encoding V5-tagged WT, CH or ΔZn PrimPol proteins were cotransfected. Data are representative of 2 experiments (b), data are pooled from 3 experiments (c). Error bars, s.d. *P<0.05, **P<0.01, *** P<0.001 (Student's t-test), NS, not significative (c).

Supplementary Figure 7 Uncropped images corresponding to the immunoblots included in main and supplementary figures.

(a) Uncropped images of Western blots in Fig. 1a. (b) Uncropped images of Western blots in Fig. 1b. (c) Uncropped images of Western blots in Fig. 2a. (d) Uncropped images of Western blots in Fig. 5e. (e) Uncropped images of Western blots in Fig. 6b. (f) Uncropped images of Western blots in Fig. 6a. (g) Uncropped images of Western blots in Supplementary Fig. 1a. (h) Uncropped images of Western blots in Supplementary Fig. 1c. (i) Uncropped images of Western blots in Supplementary Fig 2a. (j) Uncropped images of Western blots in Supplementary Fig. 3a. (k) Uncropped images of Western blots in Supplementary Fig. 3d.

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Mourón, S., Rodriguez-Acebes, S., Martínez-Jiménez, M. et al. Repriming of DNA synthesis at stalled replication forks by human PrimPol. Nat Struct Mol Biol 20, 1383–1389 (2013). https://doi.org/10.1038/nsmb.2719

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