DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Abstract

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

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Fig. 1: Genome-wide CRISPR screen reveals DYNLL1 loss causes resistance to PARPi and platinum in BRCA1-mutant HGSOCs.
Fig. 2: DYNLL1 loss leads to restoration of DNA end resection and homologous recombination.
Fig. 3: Effect of DYNLL1 on chromosomal aberrations in HGSOC samples and interaction with the DNA end-resection machinery.
Fig. 4: Identification and characterization of DYNLL1 mutants that affect genome stability in cells and DNA end resection in vitro.

Data availability

All relevant data are included in the paper and/or its Supplementary Information.

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Acknowledgements

D.C. is supported by NIH grants R01 CA208244 and R01CA142698, a Leukemia and Lymphoma Society Scholar grant, and the Claudia Adams Barr Program in Innovative Basic Cancer Research. D.C. and P.A.K. are supported by DOD W81XWH-15-0564/OC140632. Y.J.H. is supported by an AACR-AstraZeneca Ovarian Cancer Research Fellowship (17-40-12-HE). J.-Y.M. was supported by a CIHR foundation grant.

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Nature thanks T. Stracker and the anonymous reviewer(s) for their contribution to the peer review of this work.

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Contributions

Y.J.H. and D.C. designed the study with input from P.A.K. and A.D.D. Y.J.H. and K.M. performed most of the cell-based experiments with assistance from C.Y., J.B., J.M. and P.D. A.D. did the statistical analysis of images. M.-C.C., D.A.R. and J.N. conducted the in vitro studies under J.-Y.M.’s supervision. G.L. provided the guidance and reagents on the AsiSI system. J.G.D. and D.E.R. provided all of the reagents and the analysis of the CRISPR library. A.S. performed statistical and computational analysis of clinical data under S.D.’s guidance. D.C. wrote the manuscript with input from P.A.K. and A.D.D.

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Correspondence to Dipanjan Chowdhury.

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Extended data figures and tables

Extended Data Fig. 1 DYNLL1 depletion causes resistance to PARPi and cisplatin in multiple lineages.

a, Relative guide abundance before and after olaparib and cisplatin treatment in Cov362 cells (data provided in Supplementary Tables 1 and 2). b, Comparison of ATMIN and BRCA1 alterations in ovarian cancer according to the TCGA dataset24 (316 samples) from the cBioPortal. c, Survival assay of RPE1 cells treated with olaparib (left) or cisplatin (right), after transfection with non-targeting control or DYNLL1 siRNA (siCtrl or siDYNLL1). d, Immunoblot of ATMIN and DYNLL1 from Cov362 cells with deletions of ATMIN or DYNLL1 (sgATMIN or sgDYNLL1). Tubulin was used as a loading control. eg, Survival assay of BRCA1-mutant cells UWB1.289 (e), MDA-MB-236 (f) and L56Br-C1 (g) treated with olaparib or cisplatin, and transfected with control or DYNLL1 siRNA. Data are mean ± s.e.m. from three different experiments. h, Immunoblots showing depletion of DYNLL1. Experiments were repeated independently three times with similar results.

Extended Data Fig. 2 Impact of DYNLL1 on PARPi and cisplatin is specific to BRCA1-mutant cells.

a, b, Survival assay of RPE1 (a) and HeLa (b) cells transfected with BRCA1 siRNA and treated with olaparib (left) or cisplatin (right), and co-transfected with control or DYNLL1 siRNA. c, Immunoblots showing depletion of DYNLL1 and BRCA1. Experiments were repeated independently three times with similar results. #1 and #2 are independent stable clones. d, Immunoblot of tagged DYNLL1 (G, GFP; F, Flag) in Cov362 cells after deletions of ATMIN or DYNLL1 (sgATMIN or sgDYNLL1). e, Survival assay of Cov362 DYNLL1−/− clone expressing tagged DYNLL1, treated with olaparib (left) or cisplatin (right). Data are mean ± s.e.m. from three different experiments. f, Survival assay of the indicated Cov362 clones transfected with KURAMOCHI cells and control or DYNLL1 siRNA, and treated with olaparib or cisplatin. For all panels, data are mean ± s.e.m. from three different experiments. g, PFS of ovarian carcinoma patients with BRCA2 mutation based on above or below median expression values of DYNLL1 (DYNLL1-high n = 14, DYNLL1-low n = 18; source: ovarian cancer, TCGA dataset24). Statistical significance was assessed by the one-sided Mantel–Cox test.

Extended Data Fig. 3 DYNLL1 influences RAD51 foci and RPA32 foci formation in BRCA1-mutant cells.

a, b, Immunofluorescence and quantification of RAD51 foci (a, b) and RPA32 foci (c) in wild-type and DYNLL1−/− Cov362 cells exposed to 5 Gy ionizing radiation. Staining is 6 h (RAD51) and 4 h (RPA32) after ionizing radiation. In a, n = 105; ***P < 0.0001 (control versus sgDYNLL1 #1), ***P = 0.0003 (control versus sgDYNLL1 #2), P = 0.5679 (sgDYNLL1 #1 versus sgDYNLL1 #2); two-tailed unpaired Student’s t-test. In b, wild-type and DYNLL1−/− Cov362 cells were also transfected with control and BRCA1 siRNA and immunblotting was used to confirm silencing. Data are mean ± s.e.m. from three different experiments (n = 100). In c, n = 100; ***P = 0.0002 (control versus sgDYNLL1 #1), ***P < 0.0001 (control versus sgDYNLL1 #2), P = 0.5679 (sgDYNLL1 #1 versus sgDYNLL1 #2); unpaired two-tailed Student’s t-test. d, Immunoblot of wild-type and DYNLL1−/− Cov362 cells after 10 μM olaparib treatment for 48 h with indicated antibodies. Experiments were repeated independently for three times with similar results. e, Analysis of 53BP1 foci as shown in Fig. 2b from wild-type and DYNLL1−/− Cov362 cells treated with 10 µM olaparib for 24 h. Data are mean ± s.e.m. from three different experiments (n = 102 cells of each genotype). fh, Immunofluorescence (left) and quantification (right) of 53BP1 foci (f; n = 95; P = 0.1019), RPA32 foci (g; n = 100; *P = 0.0238) and RAD51 foci (h; n = 94, P = 0.3161) in RPE1 cells transfected with control or DYNLL1 siRNA exposed to 5 Gy ionizing radiation for 1 h (53BP1, f), 4 h (RPA32, g) or 6 h (RAD51, h). Statistical analyses were by unpaired two-sided Student’s t-test. For all panels, data are mean ± s.e.m. from three different experiments.

Extended Data Fig. 4 DYNLL1 regulates the DNA end-resection machinery.

a, Samples from the PAEN-AU cohort were grouped into four categories based on combinatorial high (above median) and low (below median) expression levels of BRCA1 and DYNLL1. The frequency of somatic structural variants (left) and the frequency of intrachromosomal structural variants (deletion, duplication, insertion or intrachromosomal translocation) (right) were plotted. b, Samples from the PAEN-AU (32 samples) cohort were grouped into four categories based on combinatorial high (above median) and low (below median) expression levels of BRCA1 and DYNLL1 (left) or of BRCA1 and 53BP1 (right). The frequency of structural variants (deletions, duplication, insertions or intrachromosomal translocation) with indications of homology-directed repair (≥10-bp homology) was plotted. In all box plots, the upper whisker is 1.5 × IQR more than the third quartile, and the lower whisker is 1.5 × IQR lower than the first quartile, respectively, in which the interquartile range (IQR) is the difference between the third and the first quartile (that is, the box length). Circles denote outliers. c, Quantification of mRNA levels of the indicated genes in control and ATMIN−/− (sgATMIN) cells (n = 4). Expression levels were normalized to ACTB. Data are mean ± s.e.m. from four different experiments. *P = 0.0335 and **P = 0.0038 (control versus #1 and #2, respectively, for MRE11); *P = 0.0152 and *P = 0.0257 (control versus #1 and #2, respectively, for NBN), *P = 0.0130 and *P = 0.0203 (control versus #1 and #2, respectively, for BLM), ****P < 0.0001 and *P = 0.0179 (control versus #1 and #2, respectively, for DNA2); unpaired two-sided Student’s t-test. d, Quantification of mRNA levels of the indicated genes in control and DYNLL1−/− (sgDYNLL1) Cov362 cells (n = 6). Expression levels were normalized to ACTB. Data are mean ± s.e.m. from six different experiments. ****P < 0.0001 and ****P < 0.0001 (control versus #1 and #2, respectively, for MRE11); **P = 0.0035 and **P = 0.0007 (control versus #1 and #2, respectively, for RAD50); ****P < 0.0001 and ****P < 0.0001 (control versus #1 and #2, respectively, for NBN); ****P < 0.0001 and ****P < 0.0001 (control versus #1 and #2, respectively, for BLM); ****P = 0.0002 and ****P < 0.0001 (control versus #1 and #2, respectively, for DNA2); unpaired two-sided Student’s t-test. e, Quantification of subcellular fraction of indicated proteins (n = 3) in control and DYNLL1−/− Cov362 cells. Levels of total protein and chromatin-bound protein were normalized to H2AX levels, and levels of indicated proteins in DYNLL1−/− Cov362 cells are graphically represented relative to the control Cov362 cells. Data are mean ± s.e.m. f, Flag immunoprecipitation of Flag–DYNLL1 and immunoblot with indicated antibodies. g, Immunofluorescence and quantification of DYNLL1 and γ-H2AX foci in RPE1 cells transfected with control and DYNLL1 siRNA, 1 h after 5 Gy ionizing radiation (IR). Experiments were repeated independently three times with similar results. h, Immunoblot of DYNLL1 in RPE1 cells exposed to 5 Gy ionizing radiation and subcellular fractionation at indicated times. Experiments were repeated independently three times with similar results.

Extended Data Fig. 5 Separation of the functions of DYNLL1 mutants that influence DNA end resection in vitro.

a, Structure of DYNLL1 dimer with potentially relevant residues indicated. b, Immunoprecipitation of indicated DYNLL1 mutants with 53BP1 and MRE11. Experiments were repeated independently three times with similar results. c, Immunoblot of tagged wild-type and mutant DYNLL1 in DYNLL1−/− Cov362 cells from Fig. 4b. d, Resection products of wild-type or mutant recombinant DYNLL1 (purified proteins, left panel) with MRN–RPA–BLM–DNA2 and a 32P-labelled linear 2.7-kb dsDNA substrate. Experiments were repeated independently three times with similar results. e, GST pull-down of GST-tagged mutant DYNLL1 (Ser88Asp) incubated with purified human MRE11 or human DNA2, EXO1, BLM or the human RPA trimer (RPA70–RPA32–RPA14). Experiments were repeated independently three times with similar results. f, Recombinant wild-type DYNLL1 protein was incubated with RPA and BLM and with a 32P-labelled linear 2.7-kb dsDNA substrate to monitor DNA unwinding. Experiments were repeated independently three times with similar results.

Supplementary information

Supplementary Figure 1

This file contains the uncropped scans for immunoblots, with protein sizes indicated in kDa.

Reporting Summary

Supplementary Table 1

Results of CRISPR screens for suppressors of olaparib sensitivity in BRCA1 mutant ovarian cancer cell line COV362. The data include: gene symbol, number of unique guides for the corresponding gene, ranks of each guide, DNA sequence for each corresponding guide RNA, number of most enriched guides, enrichment score, p-value, FDR, and corrected FDR (q-value). Library targeted 18,080 genes with 64,751 unique guide sequences. Statistics analysis was performed using the STARS software from the Broad Institute, Cambridge, MA. See main text and Methods for details.

Supplementary Table 2

Results of CRISPR screens for suppressors of cisplatin sensitivity in BRCA1 mutant ovarian cancer cell line COV362. The data include: gene symbol, number of unique guides for the corresponding gene, ranks of each guide, DNA sequence for each corresponding guide RNA, number of most enriched guides, enrichment score, p-value, FDR, and corrected FDR (q-value). Library targeted 18,080 genes with 64,751 unique guide sequences. Statistics analysis was performed using the STARS software from the Broad Institute. Cambridge, MA. See main text and Methods for details.

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He, Y.J., Meghani, K., Caron, M. et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563, 522–526 (2018). https://doi.org/10.1038/s41586-018-0670-5

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Keywords

  • Somatic Structural Variants
  • BRCA Mutant Cells
  • Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)
  • High-grade Serous Ovarian Carcinoma (HGSOC)
  • Homologous Recombination-mediated Repair

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