scholarly journals METTL3 promotes homologous recombination repair and modulates chemotherapeutic response by regulating the EGF/Rad51 axis

2021 ◽  
Author(s):  
Enjie Li ◽  
Mingyue Xia ◽  
Yu Du ◽  
Kaili Long ◽  
Feng Ji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Drug Response ◽  
Homologous Recombination Repair ◽  
Chemotherapeutic Drug ◽  
Chemotherapeutic Response ◽  
Recombination Repair ◽  
Pivotal Mechanism

METTL3 and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in breast cancer (BC) cells. Knockdown of METTL3 sensitized BC cells to Adriamycin (ADR) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A "reader," YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

scholarly journals Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibaut S. Matis ◽  
Nadia Zayed ◽  
Bouchra Labraki ◽  
Manon de Ladurantaye ◽  
Théophane A. Matis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Large Fraction ◽  
Homologous Recombination Repair ◽  
Mutational Signatures ◽  
Recombination Repair ◽  
Multiple Case ◽  
Gene Panels ◽  
Tumor Dna

AbstractIt was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

scholarly journals Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair

2018 ◽  
Vol 131 (23) ◽  
pp. jcs219311 ◽  
Author(s):  
Xiangduo Kong ◽  
Gladys Mae Saquilabon Cruz ◽  
Sally Loyal Trinh ◽  
Xu-Dong Zhu ◽  
Michael W. Berns ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Sister Chromatid ◽  
Homologous Recombination Repair ◽  
Recombination Repair

scholarly journals Combined homologous recombination repair deficiency and immune activation analysis for predicting intensified responses of anthracycline, cyclophosphamide and taxane chemotherapy in triple-negative breast cancer

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gaoming Liao ◽  
Zedong Jiang ◽  
Yiran Yang ◽  
Cong Zhang ◽  
Meiting Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Immune Activation ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Homologous Recombination Repair ◽  
Repair Deficiency ◽  
Recombination Repair

Abstract Background Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Methods Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. Results HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). Conclusions These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

scholarly journals PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gergely Rona ◽  
Domenico Roberti ◽  
Yandong Yin ◽  
Julia K Pagan ◽  
Harrison Homer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
Genotoxic Stress ◽  
Strand Break ◽  
Homologous Recombination Repair ◽  
Dependent Manner ◽  
Ubiquitin Ligase Complex ◽  
Recombination Repair

The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

scholarly journals Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 889 ◽  
Author(s):  
Klaudia Szymonowicz ◽  
Adam Krysztofiak ◽  
Jansje van der Linden ◽  
Ajvar Kern ◽  
Simon Deycmar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Proton Irradiation ◽  
Negative Impact ◽  
Particle Therapy ◽  
Homologous Recombination Repair ◽  
End Joining ◽  
X Ray ◽  
Recombination Repair ◽  
Non Homologous End Joining

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

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