# CBX2 phase-separation contributes to homologous recombination repair and drug resistance in ovarian cancer **Authors:** Si Sun, Lin Huang, Yujia Ma, Zheng Wei, Mengna Zhu, Mengqing Chen, Feiquan Ying, Xiaoling Zhou, Ping Yang, Yiping Wen, Qiang Yang, Liqiong Cai, Yuan Zhang, Jing Cai PMC · DOI: 10.1038/s41419-026-08605-4 · Cell Death & Disease · 2026-03-26 ## TL;DR CBX2 phase separation helps ovarian cancer cells repair DNA and resist drugs, and Ibrutinib may be an effective treatment for patients with CBX2 condensates. ## Contribution The study reveals CBX2 phase separation's role in DNA repair and drug resistance in ovarian cancer and identifies Ibrutinib as a potential treatment. ## Key findings - CBX2 condensates facilitate recruitment of DSB repair factors PARP1, 53BP1, and BRCA1 to chromatin. - Patients with condensate CBX2 have the worst prognosis, while those with non-condensate CBX2 have better outcomes. - Ibrutinib effectively inhibits HGSOC cells and organoids with CBX2 condensates. ## Abstract Drug resistance jeopardizes the prognosis of high-grade serous ovarian carcinoma (HGSOC) patients via DNA damage repair-coupled mechanism. The role of biomolecular phase separation in DNA damage repair has loomed. Here we find that CBX2 condensates are associated with drug resistance and contribute to DNA double-strand break (DSB) repair in HGSOC. Specifically, CBX2 condensates facilitate the recruitment of key DSB repair factors PARP1, 53BP1, and BRCA1 to chromatin. Patients with a CBX2-negative pattern exhibit the best prognosis, followed by those with non-condensate CBX2, while the worst outcomes are observed in patients with condensate CBX2. By drug screening, Ibrutinib is identified as an effective inhibitor of HGSOC cells and patient-derived organoids with CBX2 condensates. Overall, CBX2 phase separation enhances DSB repair-mediated drug resistance in HGSOC cells, and Ibrutinib may offer a viable therapeutic option for CBX2-positive HGSOC patients. ## Linked entities - **Genes:** CBX2 (chromobox 2) [NCBI Gene 84733], PARP1 (poly(ADP-ribose) polymerase 1) [NCBI Gene 142], TP53BP1 (tumor protein p53 binding protein 1) [NCBI Gene 7158], BRCA1 (BRCA1 DNA repair associated) [NCBI Gene 672] - **Chemicals:** Ibrutinib (PubChem CID 24821094) - **Diseases:** ovarian cancer (MONDO:0005140) - **Species:** Homo sapiens (taxon 9606) ## Full-text entities - **Genes:** NUMA1 (nuclear mitotic apparatus protein 1) [NCBI Gene 4926] {aka NMP-22, NUMA}, EPCAM (epithelial cell adhesion molecule) [NCBI Gene 4072] {aka Ber-Ep4, BerEp4, DIAR5, EGP-2, EGP314, EGP40}, PARP1 (poly(ADP-ribose) polymerase 1) [NCBI Gene 142] {aka ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1}, TOPBP1 (DNA topoisomerase II binding protein 1) [NCBI Gene 11073] {aka Dpb11, TOP2BP1}, Vim (vimentin) [NCBI Gene 22352], RAD51 (RAD51 recombinase) [NCBI Gene 5888] {aka BRCC5, FANCR, HRAD51, HsRad51, HsT16930, MRMV2}, SSB (small RNA binding exonuclease protection factor La) [NCBI Gene 6741] {aka LARP3, La, La/SSB, SSB/La}, Cdkn2a (cyclin dependent kinase inhibitor 2A) [NCBI Gene 12578] {aka ARF-INK4a, Arf, INK4a-ARF, Ink4a/Arf, MTS1, Pctr1}, NME1 (NME/NM23 nucleoside diphosphate kinase 1) [NCBI Gene 4830] {aka AWD, GAAD, NB, NBS, NDK1, NDKA}, WT1 (WT1 transcription factor) [NCBI Gene 7490] {aka AWT1, GUD, NPHS4, WAGR, WIT-2, WT-1}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, RIF1 (replication timing regulatory factor 1) [NCBI Gene 55183], Numa1 (nuclear mitotic apparatus protein 1) [NCBI Gene 101706] {aka 6720401E04Rik, NuMA}, RNF168 (ring finger protein 168) [NCBI Gene 165918] {aka RIDL, hRNF168}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, UIMC1 (ubiquitin interaction motif containing 1) [NCBI Gene 51720] {aka RAP80, X2HRIP110}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, BTK (Bruton tyrosine kinase) [NCBI Gene 695] {aka AGMX1, AT, ATK, BPK, IGHD3, IMD1}, FUS (FUS RNA binding protein) [NCBI Gene 2521] {aka ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, PWAR1 (Prader Willi/Angelman region RNA 1) [NCBI Gene 145624] {aka D15S227E, PAR-1, PAR1}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, Trp53bp1 (transformation related protein 53 binding protein 1) [NCBI Gene 27223] {aka 53BP1, Tp53bp1, m53BP1, p53BP1}, RNF112 (ring finger protein 112) [NCBI Gene 7732] {aka BFP, ZNF179}, Rad51 (RAD51 recombinase) [NCBI Gene 19361] {aka Rad51a, Reca}, BARD1 (BRCA1 associated RING domain 1) [NCBI Gene 580], H2ax (H2A.X variant histone) [NCBI Gene 15270] {aka H2A.X, H2afx, Hist5-2ax, gammaH2ax}, ATM (ATM serine/threonine kinase) [NCBI Gene 472] {aka AT1, ATA, ATC, ATD, ATDC, ATE}, H2AX (H2A.X variant histone) [NCBI Gene 3014] {aka H2A.X, H2A/X, H2AFX}, Banf1 (BAF nuclear assembly factor 1) [NCBI Gene 23825] {aka Baf, Bcrp1, L2bp1/Baf}, XRCC5 (X-ray repair cross complementing 5) [NCBI Gene 7520] {aka KARP-1, KARP1, KU80, KUB2, Ku86, NFIV}, ATR (ATR checkpoint kinase) [NCBI Gene 545] {aka FCTCS, FRP1, MEC1, SCKL, SCKL1}, CCNE1 (cyclin E1) [NCBI Gene 898] {aka CCNE, pCCNE1}, EEF1A2 (eukaryotic translation elongation factor 1 alpha 2) [NCBI Gene 1917] {aka DEE33, EEF1AL, EF-1-alpha-2, EF1A, EIEE33, HS1}, XRCC6 (X-ray repair cross complementing 6) [NCBI Gene 2547] {aka CTC75, CTCBF, G22P1, KU70, ML8, TLAA}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, FGF10 (fibroblast growth factor 10) [NCBI Gene 2255] {aka LADD3}, ERBB4 (erb-b2 receptor tyrosine kinase 4) [NCBI Gene 2066] {aka ALS19, HER4, p180erbB4}, BRD4 (bromodomain containing 4) [NCBI Gene 23476] {aka CAP, CDLS6, FSHRG4, HUNK1, HUNKI, MCAP}, MRGBP (MRG domain binding protein) [NCBI Gene 55257] {aka C20orf20, Eaf7, MRG15BP, URCC4}, CBX2 (chromobox 2) [NCBI Gene 84733] {aka CDCA6, M33, SRXY5}, Cbx2 (chromobox 2) [NCBI Gene 12416] {aka M33, MOD2, pc}, BMI1 (BMI1 proto-oncogene, polycomb ring finger) [NCBI Gene 648] {aka FLVI2/BMI1, PCGF4, RNF51, flvi-2/bmi-1}, TP53BP1 (tumor protein p53 binding protein 1) [NCBI Gene 7158] {aka 53BP1, TDRD30, p202, p53BP1}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, MDC1 (mediator of DNA damage checkpoint 1) [NCBI Gene 9656] {aka NFBD1}, WEE1 (WEE1 G2 checkpoint kinase) [NCBI Gene 7465] {aka WEE1A, WEE1hu}, BRCA1 (BRCA1 DNA repair associated) [NCBI Gene 672] {aka BRCAI, BRCC1, BROVCA1, FANCS, IRIS, PNCA4}, PCGF2 (polycomb group ring finger 2) [NCBI Gene 7703] {aka MEL-18, RNF110, TPFS, ZNF144}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, PAX8 (paired box 8) [NCBI Gene 7849] {aka PAX-8}, PRC1 (protein regulator of cytokinesis 1) [NCBI Gene 9055] {aka ASE1, MAP65}, Brca1 (breast cancer 1, early onset) [NCBI Gene 12189], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, UBE2V1 (ubiquitin conjugating enzyme E2 V1) [NCBI Gene 7335] {aka CIR1, CROC-1, CROC1, UBE2V, UEV-1, UEV1}, Ezh2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [NCBI Gene 14056] {aka Enx-1, Enx1h, KMT6, mKIAA4065}, Egfr (epidermal growth factor receptor) [NCBI Gene 13649] {aka 9030024J15Rik, Erbb, Errb1, Errp, Wa5, wa-2} - **Diseases:** Tumor (MESH:D009369), hypoxia (MESH:D000860), PDOs (MESH:C536408), DSB (MESH:D019457), EOC (MESH:D000077216), hematologic malignancies (MESH:D019337), CBX2KO (OMIM:615441), HGSOC (MESH:D010051), gynecological malignancy (MESH:D005833), breast cancers (MESH:D001943), cytotoxic (MESH:D064420) - **Chemicals:** TSA (MESH:C481298), PI (MESH:D010716), PBS (MESH:D007854), penicillin (MESH:D010406), H&E (MESH:D006371), ethanol (MESH:D000431), crystal violet (MESH:D005840), DMSO (MESH:D004121), Triton X-100 (MESH:D017830), TBS (MESH:D013725), paclitaxel (MESH:D017239), Oil (MESH:D009821), methanol (MESH:D000432), IP (MESH:C041508), paraffin (MESH:D010232), agarose (MESH:D012685), DMEM (-), SB202190 (MESH:C090942), GSK126 (MESH:C577920), Ibrutinib (MESH:C551803), citrate (MESH:D019343), PVDF (MESH:C024865), N-acetylcysteine (MESH:D000111), colchicine (MESH:D003078), streptomycin (MESH:D013307), Formalin (MESH:D005557), HOECHST33342 (MESH:C017807), Nicotinamide (MESH:D009536), HEPES (MESH:D006531), cisplatin (MESH:D002945), saline (MESH:D012965), Niraparib (MESH:C545685), TRIzol (MESH:C411644), Alexa Fluor 488 (MESH:C000711379), MTT (MESH:C070243), G418 (MESH:C010680), CaCl2 (MESH:D002122), hematoxylin (MESH:D006416), A83-01 (MESH:C507011), Tween-20 (MESH:D011136), acetic acid (MESH:D019342), CO2 (MESH:D002245), F12 (MESH:C007782), platinum (MESH:D010984), Prostaglandin E2 (MESH:D015232), sodium citrate (MESH:D000077559), paraformaldehyde (MESH:C003043), Glutamax (MESH:C054122), SDS (MESH:D012967), DAPI (MESH:C007293) - **Species:** Mycoplasma (genus) [taxon 2093], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** OVCAR — Homo sapiens (Human), Ovarian carcinoma, Cancer cell line (CVCL_3941), A2780 — Homo sapiens (Human), Ovarian endometrioid adenocarcinoma, Cancer cell line (CVCL_0134), CAOV3 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_0201), SKOV3 — Homo sapiens (Human), Ovarian serous cystadenocarcinoma, Cancer cell line (CVCL_0532), OVCAR4 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_1627), CAOVE3 — Mus musculus (Mouse), Hybridoma (CVCL_C6V6), CCK8 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_2873), BALB/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), L310KJ — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_1654), OVRCAR4 — Homo sapiens (Human), Ataxia telangiectasia syndrome, Finite cell line (CVCL_F083) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13039389/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13039389/full.md ## References 1 references — full list in the complete paper: https://tomesphere.com/paper/PMC13039389/full.md --- Source: https://tomesphere.com/paper/PMC13039389