Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks

Ha, Geun-Hyoung; Ji, Jeong‐Seon; Chae, Sunyoung; Park, Jihyun; Kim, Suhyeon; Lee, Jin-Kwan; Kim, Yonghyeon; Min, Sunwoo; Park, Jeong-Min; Kang, Tae-Hong; Lee, Ho; Cho, Hyeseong; Lee, Chang-Woo

doi:10.1038/s41467-019-09641-9

Cited by 34 publications

(42 citation statements)

References 60 publications

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“…The importance of UFMylation in ATM activation was also shown in another study by where they showed that UFL1 UFMylates meiotic recombination 11 (MRE11) at Lys 282, leading to MRN complex formation and ATM activation [25]. In the same context, showed that Pellino1, a ubiquitin ligase which responds to DNA DSBs, is involved in ATM activation through a phospho-H2AX-NBS1-ATM signaling axis [26]. These studies show that the mechanisms behind ATM activation are still being deciphered and suggest an important link to a wide range of post-translational modifications.…”

Section: Dna-pk) and (Chk1 Chk2): The Brotherhood Of Ddr Kinasesmentioning

confidence: 63%

Kinases: The "Indispensables"of the DNA Damage Response Cascade

Menon¹,

Dcona²

2019

JoLS

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The human genome is exposed to a gamut of cellular and exogenous insults on a daily basis which needs to be monitored for proper cellular functioning and survival. This surveillance is undertaken by a myriad of protein players that ensure temporal and spatial regulation of cellular homeostasis. Kinases lie at the epicenter of the DNA damage response and exhibit a dynamic functionality, from responding to the damage to regulating the role of other proteins involved in detecting and repairing the damage. Here, we review some of the key kinases involved in DNA damage response pathways and their inhibitors that are either in clinical trials or have received approval for disease treatment.

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Section: Dna-pk) and (Chk1 Chk2): The Brotherhood Of Ddr Kinasesmentioning

confidence: 63%

Kinases: The "Indispensables"of the DNA Damage Response Cascade

Menon¹,

Dcona²

2019

JoLS

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“…Mammalian cells employ two major DNA repair pathways: homologous recombination (HR) and nonhomologous end-joining (NHEJ), to maintain cell survival [29][30][31]. Error-free HR repair requires a homologous template such as a sister chromatid, whereas NHEJ joins the two ends of a DSB through a process largely independent of homology [32]. Our previous research also showed that 500 µM VPA reduces HR e ciency [16], so we next explore whether 15 µM HPTA has the same effect on the frequency of HR in the above cell models.…”

Section: Hpta Results In the Accumulation Of More Dsbs In Response Tomentioning

confidence: 99%

2-hexyl-4-pentynoic acid (HPTA), a novel radiosensitizer to breast cancer cells through increasing the instability of DNA repair proteins

Cai

Lim

Liu

et al. 2020

Preprint

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Background Breast cancer is one of the most common malignant tumors in the world which is the main cause of cancer death for women. Radiotherapy is the main treatment. Although some drugs have been found to enhance the effect of radiotherapy, there are also obvious deficiencies. Therefore, recent applied clinical research has been focusing on locating a suitable radiosensitizer to breast cancer radiotherapy. Methods MTT, clonogenic survival assays, comet assays, immunofluorescence and western blot analyses were used to detect the effect of VPA / HPTA on DNA damage induced by radiotherapy for breast cancer through a variety of cell models( MCF7, EUFA423, HCC1937, DMBA-induced rat breast cancer-derived primary culture cell and DMBA-induced transformed human normal breast cell line). At the same time, flow cytometry, immunofluorescence and western blot analyses were used to investigate the effect of VPA / HPTA on DNA damage repair induced by radiation. In vivo experiment, the effect of HPTA as radiosensitizer was investigated by DMBA-induced breast cancer in rats. Finally, the possible mechanism of HPTA acting on target protein was proved by cycloheximide chase experiment. Results In this study, a derivative of valproic acid (VPA), 2-hexyl-4-pentynoic acid (HPTA), was demonstrated for the first time that low concentration of HPTA (15 µM) has radiosensitizing properties to breast cancer cells by multiple working models of breast cancer cell lines (in vivo), equivalent to a high concentration of VPA (500 µM). Mechanistic investigations revealed that HPTA induced radiosensitivity through inhibiting the BRCA1-Rad51-mediated homologous recombination pathway. These results were further manifested in breast cancer animal model (in vitro). Most importantly, our study found that HPTA influenced the stability of BRCA1 and Rad51 proteins via shorting their half-life. Conclusions Our findings support the proposition HPTA as an alternate, safe and effective radiosensitizer to tumor cells. Targeting BRCA1-Rad51-mediated homologous recombination pathway through HPTA may be a rational strategy to improve the radiotherapeutic efficacy of breast cancer.

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“…In contrast, ATM responds to the generated DNA DSB throughout the cell cycle and promotes DSB repair. Following the detection of DNA DSBs, it has been reported that ATM is primarily activated by interacting with NBS1 from the MRN complex [107]. Oncogene activation and loss of G1 checkpoint control that drives cancer cell replication, leading to the cancer cell dependency on the S and G2/ M checkpoints and increased replication stress when cancer cells enter the S phase [108].…”

Section: Atr Mechanisms and Inhibitorsmentioning

confidence: 99%

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

et al. 2020

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Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

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Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks

Cited by 34 publications

References 60 publications

Kinases: The "Indispensables"of the DNA Damage Response Cascade

Kinases: The "Indispensables"of the DNA Damage Response Cascade

2-hexyl-4-pentynoic acid (HPTA), a novel radiosensitizer to breast cancer cells through increasing the instability of DNA repair proteins

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

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