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53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer

ABSTRACT: 53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks (DSBs), thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination (HR) in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic dsDNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer (NK) cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer (HGSOC)s and pancreatic ductal adenocarcinoma (PDAC)s, which are refractory to ICBs, revealed that lower 53BP1 levels correlated with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE237615 | GEO | 2024/07/09

REPOSITORIES: GEO

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53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination (END-seq)

Project description:53BP1 activity drives genome instability and embryonic lethality in BRCA1-deficient cells by inhibiting homologous recombination (HR).53BP1’s anti-recombinogenic functions require phosphorylation-dependent interactions with two effector complexes, PTIP and RIF1/Shieldin. While RIF1/Shieldin is thought to block 5’-3’ nucleolytic processing of DNA ends, it remains unclear how PTIP antagonizes HR. Here we show that mutation of the PTIP interaction site in 53BP1 (S25A) increases Shieldin association with DNA damage. Despite excessive Shieldin “end-blocking” activity, the mutant protein allows end resection sufficient to rescue the lethality of BRCA1D11 mice. End resection in BRCA1D1153BP1S25A mice is rewired in a manner driven by DNA2 since Shieldin blocks EXO1-mediated nucleolytic processing. Despite ample resection, mutant cells fail to complete HR, as 53BP1/Shieldin also inhibits RNF168-mediated loading of PALB2/RAD51 onto ssDNA post-resection. As a result, BRCA1D1153BP1S25A mice exhibit hallmark features of HR insufficiency, including increased developmental neuronal apoptosis, premature aging and hypersensitivity to PARP inhibitors. Disruption of Shieldin or forced targeting of PALB2 to ssDNA in BRCA1D1153BP1S25A cells restores RNF168 recruitment, RAD51 nucleofilament formation, and PARPi resistance. Our study supports a model in which RIF1/Shieldin and PTIP associate independently with 53BP1 to regulate distinct end-resection pathways, and reveals a critical function of 53BP1/Shieldin post-resection that limits RNF168-mediated loading of RAD51.

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53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination (ChIP-seq)

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RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity

Project description:The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identified a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.

2022-02-04 | PXD031311 | Pride

Role of 53BP1 in End Protection and DNA synthesis at DNA breaks [END-seq]

Project description:Double-strand break (DSB) repair choice is greatly influenced by the initial processing of DNA ends. 53BP1 limits the formation of recombinogenic single strand DNA (ssDNA) in BRCA1-deficient cells leading to defects in homologous recombination (HR). However, the exact mechanisms by which 53BP1 inhibits DSB resection remain unclear. Previous studies have identified two potential pathways: protection against exonucleases presumably through the Shieldin (SHLD) complex binding to ssDNA, and localized DNA synthesis through the (CTC1-STN1-TEN1) CST and DNA polymerase alpha (Polα) to counteract resection. We present evidence here that 53BP1-mediated exonuclease protection plays a more significant role than CST/Polα synthesis in countering hyper-resection at DSBs in G1 phase. Using a combinatorial approach of END-seq, SAR-seq, and RPA ChIP-seq, we directly assessed the extent of resection, DNA synthesis, and ssDNA, respectively, at AsiSI-induced DSBs. We show that in the presence of 53BP1, Polα-dependent DNA synthesis reduces the fraction of resected DSBs and the resection lengths. However, in the absence of 53BP1, Polα activity is sustained on ssDNA yet does not substantially counter resection. In contrast, Exo1 nuclease activity is essential for hyperresection in the absence of 53BP1. Thus, 53BP1 inhibits resection mainly through end-protection rather than by promoting fill-in.

2021-09-10 | GSE181669 | GEO

Role of 53BP1 in End Protection and DNA synthesis at DNA breaks [ChIP-seq]

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Role of 53BP1 in End Protection and DNA synthesis at DNA breaks [SAR-seq]

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Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku. B cells were stimulated to undergo class switch recombination in vitro. Chromatin from B cells was harvested 72 hours post-stimulation and used for RPA ChIP to study the extent of resection of DNA DSBs.

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A genome-wide CRISPR screen identifies ZNF251 critical for resistance to PARP inhibitors

Project description:The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially these harboring BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting accumulation of toxic DSBs. Unfortunately, PARP inhibitor (PARPi) resistance is common and develops through multiple mechanisms. Restoration of HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we undertook an unbiased approach with a CRISPR-pooled library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and confirmed its loss-of-function led to the PARPi resistance in BRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi. Taken together, our study identified a novel gene whose loss of function conferred resistance to PARPi, providing new insight into signaling pathways that contribute to acquired resistance in BRCA1-mutated breast and ovarian cancers.

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Project description:53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination, and reduced fidelity of long-range V(D)J recombination. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive, unlike 53BP1-deficient cells, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin—a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)— as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.

2018-07-26 | PXD009650 | Pride

Shieldin/CST-dependent and independent functions of 53BP1 control DNA end-joining and repair pathway choice

Project description:53BP1 regulates DNA end-joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting RIF1 and shieldin, a poorly understood DNA-binding complex. The 53BP1-RIF1-shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate non-homologous end-joining (NHEJ). However, how this axis regulates DNA end-joining and HR suppression remains unresolved. We investigated shieldin and its interplay with CST, a complex recently implicated in 53BP1-dependent activities. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination co-reliant on both complexes. DNA damage-responsive signalling promotes shieldin-CST interaction, demonstrating shieldin as a DSB-specific CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin-CST. Lastly, 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient cells independently of shieldin. These findings showcase the resilience of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.

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