Abstract
DNA double-strand breaks (DSBs) are repaired through homology-directed repair (HDR) or non-homologous end joining (NHEJ). BRCA1/2-deficient cancer cells cannot perform HDR, conferring sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). However, concomitant loss of the pro-NHEJ factors 53BP1, RIF1, REV7–Shieldin (SHLD1–3) or CST–DNA polymerase alpha (Pol-α) in BRCA1-deficient cells restores HDR and PARPi resistance. Here, we identify the TRIP13 ATPase as a negative regulator of REV7. We show that REV7 exists in active ‘closed’ and inactive ‘open’ conformations, and TRIP13 catalyses the inactivating conformational change, thereby dissociating REV7–Shieldin to promote HDR. TRIP13 similarly disassembles the REV7–REV3 translesion synthesis (TLS) complex, a component of the Fanconi anaemia pathway, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair. Importantly, TRIP13 overexpression is common in BRCA1-deficient cancers, confers PARPi resistance and correlates with poor prognosis. Thus, TRIP13 emerges as an important regulator of DNA repair pathway choice—promoting HDR, while suppressing NHEJ and TLS.
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Data availability
Mass spectrometry data have been deposited in MASSive data repository and are freely available at ftp://massive.ucsd.edu/MSV000084515/. All TCGA breast cancer data were accessed from the METABRIC study through cBioportal at https://www.cbioportal.org/study/summary?id=brca_metabric. Mutation signature data were accessed from mSignatureDB at http://tardis.cgu.edu.tw/msignaturedb/.
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Acknowledgements
We thank staff at the Structural and Chemical Biology Center at DFCI for the NMR data. This research was supported by a Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number, SU2C-AACR-DT16-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. This work was also supported by grants from the US National Institutes of Health (R37HL052725 and P01HL048546), the US Department of Defense (BM110181), the Breast Cancer Research Foundation, the Fanconi Anemia Research Fund, the Ludwig Center at Harvard and the Smith Family Foundation (to A.D.D.), the US National Institutes of Health (P01 CA203655 and R01 CA215489; to J.A.M.) and the Leukemia and Lymphoma Society (5440-16) and the Claudia Adams Barr Program in Innovative Basic Cancer Research (to P.S).
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C.S.C., P.S. and A.D.D. conceived the study. C.S.C. and P.S. performed experiments, analysed data and wrote the manuscript. K.P. and L.D.G. performed experiments and analysed data. I.C. and L.M. performed experiments. G.A. and J.A.M. performed mass spectrometry experiments. D.C. and A.D.D. advised and contributed to the manuscript.
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Extended data
Extended Data Fig. 1 Organization and physical interaction of TRIP13 with Shieldin, and lack of contribution of MAD2 to HDR repair.
a, Schematic of TRIP13 functional domains. b, Western blot of FLAG IP from HEK293T cells transfected with FLAG-empty vector or FLAG-REV7, SHLD1, SHLD2 or SHLD3. c, Repeats of pulldowns in (b) with or without DNA damage. d, Western blot FLAG-REV7 IPs showing the interaction with endogenous TRIP13 following treatment with the indicated DNA damaging agents. e, Western blot of REV7 and TRIP13 from U2OS wild type, REV7-/-, TRIP13-/-, pBabe empty vector and pBabe-TRIP13. f. Western blot showing the expression of Wild-type and E252Q ATPase-dead forms of TRIP13. g, 14-day clonogenic survival assay of U2OS cells expressing Empty vector, wild-type TRIP13 or TRIP13-E253Q treated with indicated doses of olaparib. n=3 biologically independent experiments, Empty vector vs. TRIP13 wild-type: p = 0.005, Empty vector vs. TRIP13-E253Q: p = 0.81 (2-Way ANOVA). h, 5-day cytotoxicity analysis of U2OS cells transfected with nontargeting, REV7- or MAD2-targeted siRNA and treated with indicated doses of Olaparib. n=3 biologically independent experiments, siCtrl vs siREV7: p < 0.0001, siCtrl vs. siMAD2: p = 0.12 (2-Way ANOVA). i, Western blot showing knockdown of MAD2 and REV7 in U2OS cells used for (h). j, Percentage of GFP-positive cells following infection of U2OS DR-GFP cells with I-SceI adenovirus with knockdown of BRCA1 or MAD2. n=3 biologically independent experiments, siCtrl vs. siBRCA1: p = 0.009, siCtrl vs. siMAD2: p = 0.99. k, 14-day clonogenic survival assay of wild-type, TRIP13-/- or TRIP13-/- REV7-/- U2OS cells treated with indicated doses of olaparib. n=3 biologically independent experiments, TRIP13-/- vs. TRIP13-/- REV7-/-: p = 0.02 (2-Way ANOVA). l, Western blot showing REV7-/- TRIP13-/- double knockout cell lines. m, Western blot showing overexpression of TRIP13 in HCC1937 cells. All error bars indicate SEM. All immunoblots are representative of at least 2 independent experiments.
Extended Data Fig. 2 Characterization of the REV7 conformers and REV7 seatbelt interactions.
a, Elution profile of purified REV7 upon size exclusion chromatography. b, From top to bottom: western blot of REV7 AEC fractions from total purified REV7, isolated REV7-F1, isolated REV7-F2 and isolated REV7-F1 after overnight incubation at 37 °C. c, Schematic of TRIP13 regulation of seatbelt-SBM binding. REV7 binds to REV3, SHLD3 and CAMP by adopting a closed seatbelt conformation encircling their respective SBM (in white). The REV7Δseatbelt mutant is unable to adopt the closed conformation and therefore unable to bind via its seatbelt. TRIP13 negatively regulates seatbelt-SBM interactions by promoting REV7 opening. d, Alignment of REV7 seatbelt binding motifs (SBM) from three different human proteins: REV3, SHLD3 and CAMP showing the conserved (R/K)PxxxxP(S/T) motif. e, GST pulldown of E. coli-produced GST-SHLD3 and REV7 or REV7Δseatbelt. ΔC refers to the Δseatbelt mutant form of REV7. All immunoblots and Coomassie stained gels are representative of at least 2 independent experiments.
Extended Data Fig. 3 Effect of TRIP13 on REV7 binding to Shieldin and recruitment to DNA damage.
a, Coomassie-stained gel showing purification of TRIP13 and REV7. b, Measurement of ATPase activity by ADP-Glo assay with indicated concentrations of purified TRIP13 protein. c, Western blots showing co-IP of FLAG-SHLD3 and REV7 in wild-type and TRIP13-/- U2OS and HEK293T cells. d, Western blot showing co-IP of GFP-tagged SHLD1 (S1) and SHLD3 (S3) with endogenous REV7 in wild-type or TRIP13-/- cells. e. Quantification of western blot in (d). f, Proportion of U2OS cells expressing either pBabe-empty vector or pBabe-TRIP13 with more than 5 REV7 foci. n = 3 biologically independent experiments, p = 0.02 (Student’s paired t-test, two-tailed). g, Representative pictures for (e) showing REV7 focus formation 6 h after IR treatment. (Scale bar: 10 μm) h, Chromatin fractionation of REV7 in U2OS wild-type, TRIP13-/- and REV7-/- cells with or without IR treatment. Histone H3 is used as control for chromatin isolation. i, Percentage of U2OS cells forming more than five 53BP1 foci 2 hours following IR treatment. Bars show untreated (left) and irradiated (right) for each sample. j, Percentage of U2OS cells forming greater than five RIF1 foci 2 hours following IR treatment. Bars show untreated (left) and irradiated (right) for each sample. All error bars represent SEM. All immunoblots and coomassie stained gels are representative of at least 2 independent experiments.
Extended Data Fig. 4 Effects of TRIP13 knockout and overexpression in HDR assays.
a, Quantification of resected ssDNA in U2OS cells expressing pBabe-empty vector or pBabe-TRIP13 measured by SMART assay. Lines indicate mean and SEM, n = approximately 100 fibers per genotype, p<0.0001 (Mann-Whitney test, two-tailed). b, Representative images for (a), with BrdU in exposed ssDNA tracts labeled red. (Scale bar: 1 μm) c, Proportion of U2OS cells expressing pBabe-empty vector or pBabe-TRIP13 with greater than 10 p-RPA32(S33) foci 6 hours following IR treatment. n = 3 biologically independent experiments, p = 0.002 (Student’s t-test, two-tailed). d, Western blot showing TRIP13 knockout in HeLa cells. e, Proportion of HeLa cells with greater than 10 p-RPA32(S33) foci 6 hours following IR treatment. f. Western blot showing RPA32 phosphorylation (S33) and H2AX phosphorylation, with or without irradiation in wild-type or TRIP13-/- U2OS cells, expressing Empty vector or TRIP13-E253Q. g, Proportion of U2OS cells expressing Empty vector or TRIP13 with greater than 10 RAD51 foci 6 hours following IR treatment. n = 3 biologically independent experiments, p = 0.01 (Student’s t-test, two-tailed). h, Proportion of HeLa cells with more than 10 RAD51 foci 6 hours following IR treatment. n=2 biologically independent experiments. i, Western blot showing TRIP13 knockdown for DR-GFP experiment in 4g. j, Percentage of GFP-positive cells following infection of U2OS DR-GFP cells expressing FLAG empty vector or FLAG-TRIP13 with I-SceI adenovirus. n = 3 biologically independent experiments, p = 0.05 (Student’s t-test, two-tailed). All error bars indicate SEM. All immunoblots are representative of at least 2 independent experiments.
Extended Data Fig. 5 Effects of TRIP13 deficiency in TLS assays.
a, Schematic of the SupF assay. Plasmids are damaged by exposure to a high UV dose. Damaged plasmids are transfected into HEK293T cells and allowed to replicate, accumulating mutations. Plasmids are isolated from cells and transformed into a reporter E. coli strain. Functional SupF expression allows for readthrough of a premature stop codon in the LacZ gene. Any mutations in SupF give LacZ- colonies. b, 14-day clonogenic survival assay of U2OS wild-type, TRIP13-/- or REV7-/- cell lines treated with indicated mitomycin C (MMC) doses. n=3 biologically independent experiments, Wild-type vs. TRIP13-/- #3: p = 0.19, Wild-type vs. TRIP13-/- #7: p = 0.15, Wild-type vs. REV7-/-: p < 0.0001 (2-Way ANOVA) c, 14-day clonogenic survival assay of U2OS wild-type, TRIP13-/- or REV7-/- cell lines treated with indicated UV doses. n=3 biologically independent experiments, Wild-type vs. TRIP13-/- #3: p = 0.23, Wild-type vs. TRIP13-/- #7: p = 0.21, Wild-type vs. REV7-/-: p < 0.0001 (2-Way ANOVA). d, (Top) Table summarizing effect of nontargeting, REV7- or TRIP13-targeting siRNAs on chromosome radial formation, a hallmark of FA pathway dysfunction, and premature chromatid separation (PCS), indicative of SAC dysfunction. (Bottom) Metaphase spreads from HEK293T cells transfected with specified siRNAs showing radials and PCS in boxes.
Extended Data Fig. 6 TRIP13 alterations, expression levels and effect on Olaparib resistance in cancers, cancer cell lines and a BRCA1-deficient model.
a, Summary of TRIP13 genomic alterations across various cancer types in TCGA. b, Summary of TRIP13 transcriptional alterations across various cancer types in TCGA. c, Western blot showing TRIP13 protein levels from a panel of breast and ovarian cancer cell lines and Ponceau S staining as loading control. BRCA1-mutant cell lines are indicated with arrows. d, Western blot showing knockdown of TRIP13 and REV7 in the SUM149PT cells. e, Western blot showing knockdown of REV7 and 53BP1 in SUM149PT cells. f, 14-day clonogenic survival assay of RPE-1 TP53BP1-/- and TP53BP1-/- BRCA1-/- cell lines with siRNAs targeting control, TRIP13 or REV7 and treated with indicated olaparib doses. n=3 biologically independent experiments, siCtrl vs. siREV7: p = 0.005 (2-Way ANOVA). g, 14-day clonogenic survival assay of BRCA1+/+ and BRCA1-/- cells expressing Empty vector or TRIP13 treated with indicated Olaparib doses, n=3 biologically independent experiments, BRCA1+/+ vs. BRCA1-/- +Empty vector: p <0.0001, BRCA1-/- +Empty vector vs. BRCA1-/- + TRIP13: p<0.0001 (2-Way ANOVA). All immunoblots are representative of at least 2 independent experiments.
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Clairmont, C.S., Sarangi, P., Ponnienselvan, K. et al. TRIP13 regulates DNA repair pathway choice through REV7 conformational change. Nat Cell Biol 22, 87–96 (2020). https://doi.org/10.1038/s41556-019-0442-y
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DOI: https://doi.org/10.1038/s41556-019-0442-y
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