RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence

Čekan, Pavol; Hasegawa, Keisuke; Tubman, Emily; Odde, David J.; Chen, Jin Qiu; Herrmann, Michelle A.; Kumar, Shailendra; Kaláb, Petr

doi:10.1091/mbc.e16-01-0025

Cited by 42 publications

(41 citation statements)

References 59 publications

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“…RCC1 helps establish the Ran GTP gradient necessary for nucleocyotoplasmic transport (Izaurralde et al ., ). Increased Rcc1 activity increases DNA damage repair and reduces senescence, suggesting a role in aging (Cekan et al ., ). While pathways were shared between nuclei from both tissues, the individual proteins that changed differed, which is consistent with a previous study in which aging affected the same pathways in two hind‐limb muscles but via different proteins (Chaves et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Biochemical isolation of myonuclei employed to define changes to the myonuclear proteome that occur with aging

et al. 2017

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SummarySkeletal muscle aging is accompanied by loss of muscle mass and strength. Examining changes in myonuclear proteins with age would provide insight into molecular processes which regulate these profound changes in muscle physiology. However, muscle tissue is highly adapted for contraction and thus comprised largely of contractile proteins making the nuclear proteins difficult to identify from whole muscle samples. By developing a method to purify myonuclei from whole skeletal muscle, we were able to collect myonuclei for analysis by flow cytometry, biochemistry, and mass spectrometry. Nuclear purification dramatically increased the number and intensity of nuclear proteins detected by mass spectrometry compared to whole tissue. We exploited this increased proteomic depth to investigate age‐related changes to the myonuclear proteome. Nuclear levels of 54 of 779 identified proteins (7%) changed significantly with age; these proteins were primarily involved in chromatin maintenance and RNA processing. To determine whether the changes we detected were specific to myonuclei or were common to nuclei of excitatory tissues, we compared aging in myonuclei to aging in brain nuclei. Although several of the same processes were affected by aging in both brain and muscle nuclei, the specific proteins involved in these alterations differed between the two tissues. Isolating myonuclei allowed a deeper view into the myonuclear proteome than previously possible facilitating identification of novel age‐related changes in skeletal muscle. Our technique will enable future studies into a heretofore underrepresented compartment of skeletal muscle.

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Section: Discussionmentioning

confidence: 97%

Biochemical isolation of myonuclei employed to define changes to the myonuclear proteome that occur with aging

et al. 2017

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“…RCC1 is further involved in nucleo-cytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly following mitosis 13 , 14 . Increased RCC1 expression could raise cellular RanGTP levels and enhance the function of importin β and exportin 1, which accelerate cell cycle progression and modulate cellular responses to DNA damage 15 . Loss of RCC1 might block cell cycle progression though the G1/S transition 14 .…”

Section: Introductionmentioning

confidence: 99%

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells

et al. 2018

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Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase and plays key roles in nucleo-cytoplasmic transport, mitosis, and nuclear envelope assembly. RCC1 is known to be a critical cell cycle regulator whose loss causes G1 phase arrest, but the molecular basis for this regulation is poorly understood. Furthermore, little is known about the relationship between RCC1 and carcinomas. Human papillomavirus (HPV) infection is highly associated with the development of cervical cancer. The expression and function of RCC1 in HPV-related cervical cancer and cell cycle regulation have not yet been explored. In this study, we first observed that RCC1 immunostaining was mildly increased in cervical cancer tissues and significantly upregulated in HPV E7-expressing cells; this localization was primarily nuclear. We showed that the transcription factor c-Jun transcriptionally upregulates RCC1 via a direct interaction with the RCC1 promoter. Moreover, siRNA-mediated knockdown of RCC1 inhibited G1/S cell cycle progression and DNA synthesis, while overexpression of RCC1 abrogated the G1 checkpoint. RCC1 knockdown downregulated the protein levels of the transcription factor E2F1, especially nuclear E2F1, by promoting its degradation in HPV E7-expressing cells. Overexpression of E2F1 rescued RCC1 knockdown-mediated inhibition of G1/S progression. Additionally, we showed that cyclin-dependent kinase 1 (Cdk1), a known target of E2F1, is involved in G1 checkpoint regulation, as Cdk1 knockdown hindered G1/S progression, while Cdk1 overexpression rescued RCC1 knockdown-mediated effect on G1 cell cycle progression. Furthermore, RCC1 knockdown reduced HPV E7 protein levels, which may in turn downregulate E2F1. Our study explores the function of RCC1 in G1/S cell cycle progression and suggests that RCC1 may be involved in HPV E7-mediated genomic instability.

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“…14 It has initially been identified as a regulator for the onset of chromosome condensation in the S phase. 18 Hence, RCC1 is a well-known key protein in assuring the fidelity of DNA replication and subsequent entry of faithfully replicated chromosomes into cell division. 16 RCC1 creates the anisotropy of the distribution of RanGTP (the RanGTP gradient) underlying mitotic spindle assembly and nuclear pore and nuclear envelope formation.…”

Section: Discussionmentioning

confidence: 99%

“…17 RCC1dependent activation of Ran accelerates cell cycle and DNA repair and inhibits DNA damage-induced cell senescence. 18 Hence, RCC1 is a well-known key protein in assuring the fidelity of DNA replication and subsequent entry of faithfully replicated chromosomes into cell division.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

Riahi

Radmanesh

Schürmann

et al. 2018

Intl Journal of Cancer

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Breast cancer is a genetic disease but the known genes explain a minority of cases. To elucidate the molecular basis of breast cancer in the Tunisian population, we performed exome sequencing on six BRCA1/BRCA2 mutation-negative patients with familial breast cancer and identified a novel frameshift mutation in RCC1, encoding the Regulator of Chromosome Condensation 1. Subsequent genotyping detected the 19-bp deletion in additional 5 out of 153 (3%) breast cancer patients but in none of 400 female controls (p = 0.0015). The deletion was enriched in patients with a positive family history (5%, p = 0.0009) and co-segregated with breast cancer in the initial pedigree. The mutant allele was lost in 4/6 breast tumors from mutation carriers which may be consistent with the hypothesis that RCC1 dysfunction provides a selective disadvantage at the stage of tumor progression. In summary, we propose RCC1 as a likely breast cancer susceptibility gene in the Tunisian population.

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RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence

Cited by 42 publications

References 59 publications

Biochemical isolation of myonuclei employed to define changes to the myonuclear proteome that occur with aging

Biochemical isolation of myonuclei employed to define changes to the myonuclear proteome that occur with aging

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells

Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

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