The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.
Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells
Open accessAbstract
BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR–Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, ‘Shieldin’ (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance. Through CRISPR–Cas9 screen, Dev et al. identified that SHLD1/2 inhibition contributes to PARP-inhibitor resistance. Mechanistically, SHLDs promote non-homologous end-joining and antagonize homologous recombination.
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Self-citationThe DNA-damage response in human biology and disease
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Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment
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Genome-scale CRISPR-Cas9 knockout screening in human cells
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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
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Targeting DNA damage response pathways in cancer
Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N., & Tarsounas, M. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00535-5 · Cited by 836
A decade of clinical development of PARP inhibitors in perspective
Mateo, J., Lord, C. J., Serra, V., Tutt, A., Balmaña, J., Castroviejo-Bermejo, M., Cruz, C., Oaknin, A., Kaye, S. B., & de Bono, J. S. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz192 · Cited by 743
“There is also evidence in preclinical models of the co-existence of other mechanisms of resistance involving, for example, BRCA1 restoration with the removal of barriers to DNA end resection via loss of 53BP1 or proteins from the Shieldin complex, among others [75, 76].”
BackgroundSelf-citationPARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance
Rose, M., Burgess, J. T., O’Byrne, K., Richard, D. J., & Bolderson, E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564601 · Cited by 719
PARP and PARG inhibitors in cancer treatment
Slade, D. (2020) · Genes & Development · doi:10.1101/gad.334516.119 · Cited by 667
Metadata
- Authors
- Dev, H., Chiang, T.-W. W., Lescale, C., de Krijger, I., Martin, A. G., Pilger, D., Coates, J., Sczaniecka-Clift, M., Wei, W., Ostermaier, M., Herzog, M., Lam, J., Shea, A., Demir, M., Wu, Q., Yang, F., Fu, B., Lai, Z., Balmus, G., Belotserkovskaya, R., Serra, V., O’Connor, M. J., Bruna, A., Beli, P., Pellegrini, L., Caldas, C., Deriano, L., Jacobs, J. J. L., Galanty, Y., & Jackson, S. P.
- Venue
- Nature Cell Biology
- Published
- 2018-07-18
- Volume
- 20
- Issue
- 8
- Pages
- 954-965
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2883657705
- Cited by
- 417
- References
- 70
- FWCI
- 14.49
- Type
- journal article
- Language
- en
- Open access
- green
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- Dev, H., Chiang, T.-W. W., Lescale, C., de Krijger, I., Martin, A. G., Pilger, D., Coates, J., Sczaniecka-Clift, M., Wei, W., Ostermaier, M., Herzog, M., Lam, J., Shea, A., Demir, M., Wu, Q., Yang, F., Fu, B., Lai, Z., Balmus, G., . . . Jackson, S. P. (2018). Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nature Cell Biology. https://doi.org/10.1038/s41556-018-0140-1
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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