Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).
Dias, M. P., Moser, S. C., Ganesan, S. & Jonkers, J. Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat. Rev. Clin. Oncol. 18, 773–791 (2021).
DiSilvestro, P. et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J. Clin. Oncol. 41, 609–617 (2023).
Dobzhansky, T. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics 31, 269–290 (1946).
Bridges, C. B. The origin of variations in sexual and sex-limited characters. Am. Nat. 56, 51–63 (1922).
Murai, J. et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72, 5588–5599 (2012).
Huang, D. & Kraus, W. L. The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Mol. Cell 82, 2315–2334 (2022).
Ray Chaudhuri, A. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017).
Poirier, G. G., de Murcia, G., Jongstra-Bilen, J., Niedergang, C. & Mandel, P. Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure. Proc. Natl Acad. Sci. USA 79, 3423–3427 (1982).
Kruhlak, M. J. et al. Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks. J. Cell Biol. 172, 823–834 (2006).
Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2014).
Pujade-Lauraine, E. et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1274–1284 (2017).
Mateos-Gomez, P. A. et al. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).
Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518, 258–262 (2015).
Zatreanu, D. et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021).
Paes Dias, M. et al. Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps. Mol. Cell 81, 4692–4708.e9 (2021).
Zhou, J. et al. A first-in-class polymerase θ inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).
Zong, D. et al. BRCA1 haploinsufficiency is masked by RNF168-mediated chromatin ubiquitylation. Mol. Cell 73, 1267–1281.e7 (2019).
Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010).
Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).
Boon, N. J. et al. DNA damage induces p53-independent apoptosis through ribosome stalling. Science 384, 785–792 (2024).
Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
Adelman, C. A. et al. HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis. Nature 502, 381–384 (2013).
Setton, J. et al. Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination. NPJ Breast Cancer 7, 135 (2021).
Mazouzi, A. et al. FIRRM/C1orf112 mediates resolution of homologous recombination intermediates in response to DNA interstrand crosslinks. Sci. Adv. 9, eadf4409 (2023).
Gibbs-Seymour, I., Fontana, P., Rack, J. G. M. & Ahel, I. HPF1/C4orf27 is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity. Mol. Cell 62, 432–442 (2016).
Hammond, C. M. et al. DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network. Mol. Cell 81, 2533–2548.e9 (2021).
Cook, A. J., Gurard-Levin, Z. A., Vassias, I. & Almouzni, G. A specific function for the histone chaperone NASP to fine-tune a reservoir of soluble H3–H4 in the histone supply chain. Mol. Cell 44, 918–927 (2011).
Osakabe, A. et al. Nucleosome formation activity of human somatic nuclear autoantigenic sperm protein (sNASP). J. Biol. Chem. 285, 11913–11921 (2010).
Hormazabal, J. et al. Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control. Nucleic Acids Res. 50, 1875–1887 (2022).
Richardson, R. T. et al. Characterization of the histone H1-binding protein, NASP, as a cell cycle-regulated somatic protein. J. Biol. Chem. 275, 30378–30386 (2000).
Liu, C. P. et al. Distinct histone H3–H4 binding modes of sNASP reveal the basis for cooperation and competition of histone chaperones. Genes Dev. 35, 1610–1624 (2021).
Bao, H. et al. NASP maintains histone H3–H4 homeostasis through two distinct H3 binding modes. Nucleic Acids Res. 50, 5349–5368 (2022).
Jaspers, J. E. et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 3, 68–81 (2013).
Staaf, J. et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat. Med. 25, 1526–1533 (2019).
Harvey-Jones, E. et al. Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer. Ann. Oncol. 35, 364–380 (2024).
Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018).
Stewart-Morgan, K. R. & Groth, A. Profiling chromatin accessibility on replicated DNA with repli-ATAC-seq. Methods Mol. Biol. 2611, 71–84 (2023).
Lim, P. X., Zaman, M., Feng, W. & Jasin, M. BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair. Mol. Cell 84, 447–462.e10 (2024).
Xia, Y. et al. RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis. J. Exp. Med. 214, 1843–1855 (2017).
Singh, R. K., Kabbaj, M. H., Paik, J. & Gunjan, A. Histone levels are regulated by phosphorylation and ubiquitylation-dependent proteolysis. Nat. Cell Biol. 11, 925–933 (2009).
Shroff, M., Knebel, A., Toth, R. & Rouse, J. A complex comprising C15ORF41 and codanin-1: the products of two genes mutated in congenital dyserythropoietic anaemia type I (CDA-I). Biochem. J. 477, 1893–1905 (2020).
Hogan, A. K. et al. UBR7 acts as a histone chaperone for post-nucleosomal histone H3. EMBO J. 40, e108307 (2021).
Hauer, M. H. et al. Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates. Nat. Struct. Mol. Biol. 24, 99–107 (2017).
Tsukuda, T., Fleming, A. B., Nickoloff, J. A. & Osley, M. A. Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiae. Nature 438, 379–383 (2005).
Verma, P. et al. ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells. Nat. Cell Biol. 23, 160–171 (2021).
Hewitt, G. et al. Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD. Mol. Cell 81, 767–783.e11 (2021).
Gogola, E. et al. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 33, 1078–1093.e12 (2018).
Muthurajan, U. M. et al. Automodification switches PARP-1 function from chromatin architectural protein to histone chaperone. Proc. Natl Acad. Sci. USA 111, 12752–12757 (2014).
Challa, K. et al. Damage-induced chromatome dynamics link ubiquitin ligase and proteasome recruitment to histone loss and efficient DNA repair. Mol. Cell 81, 811–829.e6 (2021).
Campos, E. I. et al. The program for processing newly synthesized histones H3.1 and H4. Nat. Struct. Mol. Biol. 17, 1343–1351 (2010).
Wang, H., Walsh, S. T. & Parthun, M. R. Expanded binding specificity of the human histone chaperone NASP. Nucleic Acids Res. 36, 5763–5772 (2008).
Plessier, A. et al. Proteomic profiling of UV damage repair patches uncovers histone chaperones with central functions in chromatin repair. Preprint at bioRxiv https://doi.org/10.1101/2024.08.23.609352 (2024).
Lee, S. B. et al. Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Sci. Adv. 4, eaat4985 (2018).
Ali-Fehmi, R. et al. Analysis of the expression of human tumor antigens in ovarian cancer tissues. Cancer Biomark. 6, 33–48 (2010).
Poli, J., Gasser, S. M. & Papamichos-Chronakis, M. The INO80 remodeller in transcription, replication and repair. Phil. Trans. R. Soc. B https://doi.org/10.1098/rstb.2016.0290 (2017).
Nishi, R. et al. Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nat. Cell Biol. 16, 1016–1026 (2014).
Zimmermann, M. et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 559, 285–289 (2018).
Reveron-Gomez, N. et al. Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication. Mol. Cell 72, 239–249.e5 (2018).
Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963.e11 (2019).
Li, N. et al. Parental histone transfer caught at the replication fork. Nature 627, 890–897 (2024).
Petryk, N. et al. MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science 361, 1389–1392 (2018).
Carette, J. E. et al. Generation of iPSCs from cultured human malignant cells. Blood 115, 4039–4042 (2010).
Barazas, M. et al. Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors. Cancer Res. 79, 452–460 (2019).
Drean, A. et al. Modeling therapy resistance in BRCA1/2-mutant cancers. Mol. Cancer Ther. 16, 2022–2034 (2017).
Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods 17, 41–44 (2020).
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
Hughes, C. S. et al. Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat. Protoc. 14, 68–85 (2019).
MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26, 966–968 (2010).
Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).
Servant, N. et al. HiC-Pro: an optimized and flexible pipeline for Hi-C data processing. Genome Biol. 16, 259 (2015).
Flyamer, I. M. et al. Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110–114 (2017).
Brockmann, M. et al. Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. Nature 546, 307–311 (2017).
Bhin, J. et al. Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. Cell Rep. 42, 112538 (2023).
Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016).
Dreyer, J. et al. Acute multi-level response to defective de novo chromatin assembly in S-phase. Mol. Cell 84, 4711–4728.e10 (2024).
Haarhuis, J. H. I. et al. A Mediator–cohesin axis controls heterochromatin domain formation. Nat. Commun. 13, 754 (2022).
Luna-Vargas, M. P. et al. Enabling high-throughput ligation-independent cloning and protein expression for the family of ubiquitin specific proteases. J. Struct. Biol. 175, 113–119 (2011).
