PERIOD 2 regulates low-dose radioprotection via PER2/pGSK3β/β-catenin/Per2 loop

Alexandrou, Aris T.; Duan, Yixin; Xu, Shanxiu; Tepper, Clifford G.; Fan, Ming; Tang, Jason; Berg, Jonathan; Basheer, Wassim; Valicenti, Tyler; Wilson, Paul F.; Coleman, Matthew A.; Vaughan, Andrew T M; Fu, Loning; Grdina, David J.; Murley, Jefferey; Wang, Ai‐Jun; Woloschak, Gayle E.; Li, Jian Jian

doi:10.1016/j.isci.2022.105546

Cited by 7 publications

(3 citation statements)

References 65 publications

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“…21) Moreover, we also demonstrated that zinc-induced toxicity was protected by overexpression of Per2 in Hepa1-6 cells. 13) These data suggest that clock genes act as antioxidant proteins 22,23) and Bmal1/Clock expression levels affect 4-BrCAinduced diurnal renal toxicity.…”

Section: Resultsmentioning

confidence: 94%

Involvement of Bmal1 and Clock in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Yoshioka

Yokota²,

Tominaga

et al. 2023

Biological & Pharmaceutical Bulletin

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Circadian rhythms are endogenous oscillators that regulate 24 h behavioral and physiological processes. Our previous investigation demonstrated that bromobenzene metabolite (4-bromocatechol: 4-BrCA) exhibited chronotoxicity (i.e., the nephrotoxicity induced by 4-BrCA was observed during the dark phase, while not observed at light phase in mice). However, the molecular mechanism is still unknown. The aim of the present study is to investigate the cellular molecule(s) involved in the 4-BrCA-induced nephrotoxicity using mouse renal cortex tubular cell lines (MuRTE61 cells). We found that 4-BrCA showed dose dependent (0.01-1 mM) cell proliferation defect in MuRTE61 cells. By treating with 0.03 mM 4-BrCA, we demonstrated that major clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) were significantly downregulated. Interestingly, the expression levels of two genes, Bmal1 and Clock, continued to decrease after 3 h of treatment with 4-BrCA, while Cry1, Per1, and Per2 were unchanged until 24 h of treatment. Moreover, BMAL1 and CLOCK levels are higher at light phase. We speculated that BMAL1 and CLOCK might function defensively against 4-BrCA-induced nephrotoxicity since the expression levels of Bmal1 and Clock were rapidly decreased. Finally, overexpression of Bmal1 and Clock restored 4-BrCA-induced cell proliferation defect in MuRTE61 cells. Taken together, our results suggest that Bmal1 and Clock have protective roles against 4-BrCA-induced nephrotoxicity.

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Section: Resultsmentioning

confidence: 94%

Involvement of Bmal1 and Clock in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Yoshioka

Yokota²,

Tominaga

et al. 2023

Biological & Pharmaceutical Bulletin

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“…41 In addition, PER2 ensures mitochondrial homeostasis and activates the GSK3β/β-catenin signaling pathway due to increased proliferative activity. 42 Taken as a whole, we hypothesize that conversely, the lack of PER2 may contribute to the improvement of skin tissue repair.…”

Section: Discussionmentioning

confidence: 94%

Clock gene Per2 modulates epidermal tissue repair in vivo

Yujra,

Silveira,

Ribeiro

et al. 2024

J of Cellular Biochemistry

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Wound healing can be influenced by genes that control the circadian cycle, including Per2 and BMAL1, which coordinate the functions of several organs, including the skin. The aim of the study was to evaluate the role of PER2 during experimental skin wound healing. Two groups (control and Per2‐KO), consisting of 14 male mice each, were anesthetized by inhalation, and two 6 mm wounds were created on their dorsal skin using a punch biopsy. A silicone ring was sutured around the wound perimeter to restrict contraction. The wound healing process was clinically measured daily (closure index) until complete wound repair. On Day 6, histomorphometric analysis was performed using the length and thickness of the epithelial migration tongue, in addition to counting vessels underlying the lesion by immunofluorescence assay and maturation of collagen fibers through picrosirius staining. Bromodeoxyuridine (BrdU) incorporation and quantification were performed using the subcutaneous injection technique 2 h before euthanasia and through immunohistochemical analysis of the proliferative index. In addition, the qualitative analysis of myofibroblasts and periostin distribution in connective tissue was performed by immunofluorescence. Statistically significant differences were observed in the healing time between the experimental groups (means: 15.5 days for control mice and 13.5 days for Per2‐KO; p = 0.001). The accelerated healing observed in the Per2‐KO group (p < 0.05) was accompanied by statistical differences in wound diameter and length of the migrating epithelial tongue (p = 0.01) compared to the control group. Regarding BrdU immunoreactivity, higher expression was observed in the intact epithelium of Per2‐KO animals (p = 0.01), and this difference compared to control was also present, to a lesser extent, at the wound site (p = 0.03). Immunofluorescence in the connective tissue underlying the wound showed a higher angiogenic potential in the Per2‐KO group in the intact tissue area and the wound region (p < 0.01), where increased expression of myofibroblasts was also observed. Qualitative analysis revealed the distribution of periostin protein and collagen fibers in the connective tissue underlying the wound, with greater organization and maturation during the analyzed period. Our research showed that the absence of the Per2 gene positively impacts the healing time of the skin in vivo. This acceleration depends on the increase of epithelial proliferative and angiogenic capacity of cells carrying the Per2 deletion.

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“…Previous work uncovered that the maintenance of genomic integrity and cancer progression are tightly linked to the circadian clock [41][42][43] . In general, genes involved in DNA repair pathways are transcriptionally regulated by the circadian clock 42,[44][45][46][47][48][49] . Here we found that in human cells, the PERIOD complex is directly targeted at DSBs.…”

Section: Discussionmentioning

confidence: 99%

Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope

Le Bozec,

Guitton-Sert,

Collins

et al. 2023

Preprint

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Repair of DNA Double-Strand Breaks (DSBs) produced in transcriptionally active chromatin occurs through a poorly characterized pathway called Transcription-Coupled DSB repair (TC-DSBR). Here, using a screening approach scoring multiple outputs in human cells, we identified the PER complex, a key module ensuring circadian oscillations, as a novel TC-DSBR player. Circadian rhythm has been involved in repair of UV-induced DNA damage but very little is known about its contribution to DSB repair pathways. We show that the PER complex is recruited at DSBs occurring in transcribed loci and we further found that the core protein PER2 contributes to targeting TC-DSBs at the nuclear envelope (NE) and to foster RAD51-mediated repair. PER2 deficiency triggers decreased DSB anchoring to the NE, resulting in an increase of DSB clustering and translocation frequency. In agreement, we found that the circadian clock also regulates DSB anchoring to the NE and RAD51 assembly. In conclusion, our study provides a direct link between the circadian rhythm and the response to DSBs occurring in active genes, opening new therapeutic strategies for chemotherapies based on topoisomerase poisons that mostly induce DSBs in active loci.

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PERIOD 2 regulates low-dose radioprotection via PER2/pGSK3β/β-catenin/Per2 loop

Cited by 7 publications

References 65 publications

Involvement of <i>Bmal1</i> and <i>Clock</i> in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Involvement of <i>Bmal1</i> and <i>Clock</i> in Bromobenzene Metabolite-Induced Diurnal Renal Toxicity

Clock gene Per2 modulates epidermal tissue repair in vivo

Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope

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