Inhibitory effect of uranyl nitrate on DNA double-strand break repair by depression of a set of proteins in the homologous recombination pathway

Jin, Feng; Ma, Teng; Guan, Hua; Yang, Zhihua; Liu, Xiaodan; Wang, Yu; Jiang, Yiguo; Zhou, Ping‐Kun

doi:10.1039/c7tx00125h

Cited by 15 publications

(16 citation statements)

References 39 publications

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“…An ImageQuant LAS500 system (Molecular Dynamics, Sunnyvale, CA, USA) was used to visualize the bands. Details of the Western blot analysis can be found in our previous publications 34 , 40 – 43 .…”

Section: Methodsmentioning

confidence: 99%

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

et al. 2020

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Authophagy and G2/M arrest are two important mechanistic responses of cells to ionizing radiation (IR), in particular the IR-induced fibrosis. However, what interplayer and how it links the autophagy and the G 2 /M arrest remains elusive. Here, we demonstrate that the autophagy-related protein BECN1 plays a critical role in ionizing radiation-induced G 2 /M arrest. The treatment of cells with autophagy inhibitor 3-methyladenine (3-MA) at 0–12 h but not 12 h postirradiation significantly sensitized them to IR, indicating a radio-protective role of autophagy in the early response of cells to radiation. 3-MA and BECN1 disruption inactivated the G 2 /M checkpoint following IR by abrogating the IR-induced phosphorylation of phosphatase CDC25C and its target CDK1, a key mediator of the G 2 /M transition in coordination with CCNB1. Irradiation increased the nuclear translocation of BECN1, and this process was inhibited by 3-MA. We confirmed that BECN1 interacts with CDC25C and CHK2, and which is mediated the amino acids 89–155 and 151–224 of BECN1, respectively. Importantly, BECN1 deficiency disrupted the interaction of CHK2 with CDC25C and the dissociation of CDC25C from CDK1 in response to irradiation, resulting in the dephosphorylation of CDK1 and overexpression of CDK1. In summary, IR induces the translocation of BECN1 to the nucleus, where it mediates the interaction between CDC25C and CHK2, resulting in the phosphorylation of CDC25C and its dissociation from CDK1. Consequently, the mitosis-promoting complex CDK1/CCNB1 is inactivated, resulting in the arrest of cells at the G 2 /M transition. Our findings demonstrated that BECN1 plays a role in promotion of radiation-induced G2/M arrest through regulation of CDK1 activity. Whether such functions of BECN1 in G2/M arrest is dependent or independent on its autophagy-related roles is necessary to further identify.

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Section: Methodsmentioning

confidence: 99%

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

et al. 2020

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“…7 On a molecular level, chemical uranium exposure has been found to suppress the repair pathways of doublestrand breaks (DSBs) in DNA, leading to cell death and genomic instability. 8 Through ionizing radiation, the homologous recombination (HR) and the non-homologous end-joining (NHEJ) repair pathways are impeded due to the damage to critical repair proteins involved in the processes. 8 However, not only are the repair pathways damaged, but the introduction of uranyl ions correlates to a higher incidence of DSBs as well.…”

Section: Introductionmentioning

confidence: 99%

“…8 Through ionizing radiation, the homologous recombination (HR) and the non-homologous end-joining (NHEJ) repair pathways are impeded due to the damage to critical repair proteins involved in the processes. 8 However, not only are the repair pathways damaged, but the introduction of uranyl ions correlates to a higher incidence of DSBs as well. 8 The consequent release of hydrogen peroxide introduces the loss of function to component proteins of DNA damage repair.…”

Section: Introductionmentioning

confidence: 99%

“…8 However, not only are the repair pathways damaged, but the introduction of uranyl ions correlates to a higher incidence of DSBs as well. 8 The consequent release of hydrogen peroxide introduces the loss of function to component proteins of DNA damage repair. 9 A double-strand break (DSB) is extreme damage to a DNA strand, where both strands of dual-stranded DNA are split at a certain point, which consequents genomic instability and cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Analyzing the effects of uranium on DNA damage response and unequal exposure in native populations

Pandey

Broad

2022

J Stud Res

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Uranium, a widely sought resource to produce nuclear energy, is a radioactive element that has been mined in open areas around the United States. Human exposure to uranium poses serious health risks, like cancer, organ function loss, and whole bodily debilitation. However, Native Americans are and have been greater exposed to uranium due to mines’ presence on reservations, and thus these risks incline towards such demographics. The National Institute of Health highlights this environmentally unjust exposure as a public health crisis, as uranium exposure damages critical repair pathways needed to repair DNA damage, which can lead to genomic instability and carcinogenesis. This paper attempts to create both an understanding of the molecular-scale damage uranium causes in the form of damaging non-homologous end-joining and homologous recombination pathways, while also covering a broader perspective of how indigenous peoples of America face a serious risk of such damage from their heightened exposure. First, the increased exposure risk in native communities is discussed by covering articles from government surveys, communications, and studies that gauge the danger of uranium concentrations in the environmental systems of Native nations. In the DNA repair portion, studies focusing on damage to key repair proteins in the DNA repair pathway, like the loss of zinc in its respective motif on the PARP-1 protein, and the increase of ROS causing oxidative stress in cells, pointing to the previously mentioned instability, are covered, and their methods and findings are presented.

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“…DNA double-strand breaks (DSBs) are among the most lethal types of DNA damage. Failure to properly repair DSBs leads to chromosomal aberrations, an overall increase in genomic instability and cell death [1][2][3][4][5]. There are two major mechanistic pathways in mammalian cells to repair DSBs: error-prone non-homologous end-joining (NHEJ) or error-free homologous recombination (HR) [6,7].…”

Section: Introductionmentioning

confidence: 99%

RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase

et al. 2019

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End resection of DNA double-strand breaks (DSBs) to form 3′ single-strand DNA (ssDNA) is critical to initiate the homologous recombination (HR) pathway of DSB repair. HR pathway is strictly limited in the G1-phase cells because of lack of homologous DNA as the templates. Exonuclease 1 (EXO1) is the key molecule responsible for 3′ ssDNA formation of DSB end resection. We revealed that EXO1 is inactivated in G1-phase cells via ubiquitination-mediated degradation, resulting from an elevated expression level of RING-box protein 1 (RBX1) in G1 phase. The increased RBX1 significantly prompted the neddylation of Cullin1 and contributed to the G1 phase-specific degradation of EXO1. Knockdown of RBX1 remarkedly attenuated the degradation of EXO1 and increased the end resection and HR activity in γ-irradiated G1-phase cells, as demonstrated by the increased formation of RPA32, BrdU, and RAD51 foci. And EXO1 depletion mitigated DNA repair defects due to RBX1 reduction. Moreover, increased autophosphorylation of DNA-PKcs at S2056 was found to be responsible for the higher expression level of the RBX1 in the G1 phase. Inactivation of DNA-PKcs decreased RBX1 expression, and simultaneously increased EXO1 expression and DSB end resection in G1-phase cells. This study demonstrates a new mechanism for restraining the HR pathway of DNA DSB repair in G1 phase via RBX1-prompted inactivation of EXO1.

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Inhibitory effect of uranyl nitrate on DNA double-strand break repair by depression of a set of proteins in the homologous recombination pathway

Cited by 15 publications

References 39 publications

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

Analyzing the effects of uranium on DNA damage response and unequal exposure in native populations

RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase

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