DNA repair最新文献

SWI/SNF chromatin remodelers hydrolyze ATP to modulate chromatin accessibility and are mutated in up to 20 % of human cancers. The development of ATPase inhibitors and proteolysis targeting chimeras (PROTACs) have shown that SWI/SNF complexes can be therapeutic targets against cancers that require MYC expression for their survival (e.g., leukemias, prostate cancer, uveal melanoma). In this study we show that for cancers that do not depend on MYC expression, inhibition of both SWI/SNF ATPases by BRM014 impairs homologous recombination (HR) and sensitizes U2OS osteosarcoma cells and MDA-MB-231 triple negative breast cancer cells to chemotherapeutic agents that induce DNA double strand breaks (DSBs) and importantly, to PARP inhibitors (PARPi). BRM014 impaired DSB repair and the clearance of γH2AX foci. Moreover, BRM014 stimulated the use of non-homologous end joining (NHEJ) for DSB repair. Finally, BRM014 alone or in combination with olaparib also increased the frequency of micronuclei formation and activated the cGAS/STING response mediated by the activation of NFκB. Similar results were observed by inducing the degradation of both SWI/SNF ATPases by a PROTAC (AU-15330), which impaired the repair of DSBs, sensitized cells to DNA damage and PARPi. This study shows that inhibition or degradation of both SWI/SNF ATPases enhances the effects of chemotherapy, and activates the cGAS/STING response, which is associated with better therapeutic outcomes. This study shows that SWI/SNF chromatin remodelers are an important target to enhance the effects of chemotherapy and can affect the choice of DSB repair pathway.

Toxoplasma gondii is an obligate intracellular parasite with a high replication rate that can lead to DNA replicative stress, in turn associated with the generation of DNA double-strand breaks (DSBs). Cells have two main pathways to repair DSBs: non-homologous end joining and homologous recombination repair (NHEJ and HRR respectively). RAD51 is the key recombinase in the HRR pathway. In this work, we achieved endogenous tagging of the RAD51 gene using the Auxin Inducible Degron (AID) system, to generate the clonal line RH RAD51^HA-AID. Here we demonstrate that RAD51 is expressed in replicative tachyzoites and establishes damage foci. Auxin-induced knock-down (KD) affects the correct replication of tachyzoites which show loss of synchronization. The use of the RAD51 inhibitor B02 also affects parasite growth, with an IC₅₀ of 4.8 µM. B02 produced alterations in tachyzoite replication and arrest in the S phase of the cell cycle. Additionally, B02 induced tachyzoite to bradyzoite differentiation showing small cyst-like structures. In conclusion, RAD51 is necessary for maintaining proper tachyzoite replication under normal growth conditions, supporting that genome instability occurs during the cell cycle. Our findings also suggest that DNA replication stress can induce bradyzoite differentiation.

DNA base excision repair (BER) is an evolutionarily conserved and essential DNA repair mechanism that acts as the major surveillance system for base lesions caused by endogenous and exogenous attacks. Therefore, BER is required for maintaining genomic stability under both physiological and pathological conditions. In this paper, we provide a brief review of the germline and somatic alterations of BER in cancer, with a particular focus on the core enzyme apurinic/ apyrimidinic endonuclease 1 (APE1), encoded by APEX1, and the mechanistic relationship to the development and treatment of cancer. Additionally, the review discusses the latest advances in BER-associated detection technologies and their potential clinical applications, underscoring the therapeutic potential of targeting BER for cancer prevention and intervention.

Over the past few decades, unbiased approaches such as genetic screening and protein affinity purification have unveiled numerous proteins involved in DNA double-strand break (DSB) repair and maintaining genome stability. However, despite our knowledge of these protein factors, the underlying molecular mechanisms governing key cellular events during DSB repair remain elusive. Recent evidence has shed light on the role of non-protein factors, such as RNA, in several pivotal steps of DSB repair. In this review, we provide a comprehensive summary of these recent findings, highlighting the significance of ribosomal RNA (rRNA) as a critical mediator of DNA damage response, meiosis, and mitosis. Moreover, we discuss potential mechanisms through which rRNA may influence genome integrity.