C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex

Bai, Yongtai; Wang, Weibin; Li, Siyu; Zhan, Jianming; Li, Hanxiao; Zhao, Meimei; Zhou, Xiao Albert; Li, Shiwei; Li, Xiaoman; Huo, Yansong; Shen, Qinjian; Zhou, Mei; Zhang, Hongquan; Luo, Jianyuan; Sung, Patrick; Zhu, Wei‐Guo; Xu, Xingzhi; Wang, Jiadong

doi:10.1016/j.molcel.2019.06.023

Cited by 55 publications

(45 citation statements)

References 67 publications

(91 reference statements)

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“…ATR was included in the screen a positive control for essential genes since its deletion is lethal is several cell lines due to its role in replication and the DNA damage response (Cimprich and Cortez, 2008; Flynn and Zou, 2011). Interestingly, C1QBP, a complement gene which was recently shown to play a role in the DNA damage response by modulating DNA resection, was essential in a number of cell lines, further validating our screening approach (Bai et al, 2019)( Figure 1A ) (Supplementary Table 1) .…”

Section: Resultssupporting

confidence: 72%

“…C5aR1 is the most advanced complement target in the oncology space with preclinical and clinical trial efforts mainly focused on blocking C5aR1 to improve anti-tumor immunity (Ajona et al, 2017; Markiewski et al, 2008; Massard et al, 2019; Wang et al, 2016). However, given the recently discovered autocrine and intracellular cancer-cell intrinsic roles of complement system proteins, it is important to also investigate the contribution of these functions to tumor responses (Bai et al, 2019; Block et al, 2019; Cho et al, 2014; Olcina et al, 2020). The discovery of cancer cell intrinsic functions that can potentiate anti-tumor responses without having to rely on increased T-cell infiltration would be particularly beneficial, especially in the context of so-called “cold” tumors (Duan et al, 2020; Roumenina et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Olcina

Melemenidis

Nambiar

et al. 2020

Preprint

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Engaging innate immune pathways is emerging as a productive way of achieving durable anti-tumor responses. However, systemic administration of these therapies can result in toxicity, deemed to be particularly problematic when combined with current standard-of-care cytotoxic treatments such as radiotherapy. Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies, however, few pre-clinical studies investigate both tumor and normal tissue responses in detail. Here we show that targeting innate immune receptor C5aR1 improves tumor radiation response while reducing radiation-induced normal tissue toxicity, thereby increasing the therapeutic window. The potent and orally active C5aR1 inhibitor, PMX205, increases IL-10 secretion, which attenuates RelA phosphorylation and enhances apoptosis in tumor cells. Importantly, targeting C5aR1 improves tumor radiation response even in the presence of reduced CD8+ T-cell infiltration, suggesting that this is a good target even in tumors displaying features of T-cell deficiency or exclusion. Furthermore, we find that C5aR1 depletion results in decreased small intestinal histologic damage, crypt cell apoptosis and increased survival of mice following irradiation. Using a preclinical murine model allowing the simultaneous assessment of tumor and normal tissue radiation responses, we show that PMX205 treatment reduces histological and functional markers of small-bowel toxicity while affording a positive tumor response. Our data, therefore, suggest that targeting C5aR1 could be a promising approach for increasing the therapeutic window of radiotherapy.

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Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Olcina

Melemenidis

Nambiar

et al. 2020

Preprint

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“…Conditional inactivation of MRE11 in germ cells can be performed in future to examine this possibility. C1QBP, a recently identified binding partner of MRE11 and RAD50, might mediate the residual MRE11 activity on meiotic chromosomes in the absence of NBS1 [57]. Besides being important for repairing SPO11-linked DSBs, the NBS1 ortholog XRS2 in yeast is also required for the formation of meiotic SPO11-linked DSBs [23].…”

Section: Discussionmentioning

confidence: 99%

NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis

Zhang

Tang

et al. 2020

Cell Death Differ

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DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic cells, MRE11-RAD50-NBS1 (MRN) complex-dependent DNA end resection is a prerequisite for HR repair, especially for DSBs that are covalently linked with proteins or chemicals. Interestingly, all meiotic DSBs are linked with SPO11 after being generated. Although MRN complex's function in meiotic DSB repair has been established in lower organisms, the role of MRN complex in mammalian meiotic DSB repair is not clear. Here, we show that MRN complex is essential for repairing meiotic SPO11-linked DSBs in male mice. In male germ cells, conditional inactivation of NBS1, a key component of MRN complex, causes dramatic reduction of DNA end resection and defective HR repair in meiotic prophase. NBS1 loss severely disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility in mice. Unlike in somatic cells, the recruitment of NBS1 to SPO11-linked DSB sites is MDC1-independent but requires other phosphorylated proteins. Collectively, our study not only reveals the significance of MRN complex in repairing meiotic DSBs but also discovers a unique mechanism that recruits MRN complex to SPO11-linked DSB sites.

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“…However, no associations between these two pathways and how they may cooperate to regulate apoptosis have been suggested in a cancer context, which likely reflects the fact that intracellular roles for complement proteins have only recently been considered (Liszewski et al, 2013;Arbore et al, 2017;Elvington et al, 2017;Kremlitzka et al, 2019). Of note, a recent study reported that complement factor properdin may act as a tumor suppressor in breast cancer models by upregulating ER-activated pro-apoptotic transcription factor DDIT3 (Block et al, 2019 (Bai et al, 2019). These studies, like ours, highlight the importance of investigating intracellular functions of complement proteins.…”

Section: Discussionmentioning

confidence: 99%

Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis

et al. 2020

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Summary The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner and C4BPA mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific C4BPA mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis in vitro and in vivo . Mechanistically, sensitive C4BPA mutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis.

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C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex

Abstract: Highlights d C1QBP stabilizes the MRE11 protein by forming the MRC complex with MRE11/RAD50 d C1QBP inhibits MRE11 exonuclease activity by preventing its binding to DNA d Appropriate C1QBP levels are essential for genomic stability and DNA repair

Cited by 55 publications

References 67 publications

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis

Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis

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