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Phosphorylation of DNA-binding domains of CLOCK-BMAL1 complex for PER-dependent inhibition in circadian clock of mammalian cells

DC Field Value Language
dc.contributor.authorOtobe, Yuta-
dc.contributor.authorEui Min Jeong-
dc.contributor.authorIto, Shunsuke-
dc.contributor.authorShinohara, Yuta-
dc.contributor.authorKurabayashi, Nobuhiro-
dc.contributor.authorAiba, Atsu-
dc.contributor.authorFukada, Yoshitaka-
dc.contributor.authorJae Kyoung Kim-
dc.contributor.authorYoshitane, Hikari-
dc.date.accessioned2024-12-12T07:36:36Z-
dc.date.available2024-12-12T07:36:36Z-
dc.date.created2024-06-10-
dc.date.issued2024-06-
dc.identifier.issn0027-8424-
dc.identifier.urihttps://pr.ibs.re.kr/handle/8788114/15829-
dc.description.abstractIn mammals, CLOCK and BMAL1 proteins form a heterodimer that binds to E-box sequences and activates transcription of target genes, including Period (Per). Translated PER proteins then bind to the CLOCK-BMAL1 complex to inhibit its transcriptional activity. However, the molecular mechanism and the impact of this PER-dependent inhibition on the circadian clock oscillation remain elusive. We previously identified Ser38 and Ser42 in a DNA-binding domain of CLOCK as phosphorylation sites at the PER-dependent inhibition phase. In this study, knockout rescue experiments showed that nonphosphorylatable (Ala) mutations at these sites shortened circadian period, whereas their constitutive-phospho-mimetic (Asp) mutations completely abolished the circadian rhythms. Similarly, we found that nonphosphorylatable (Ala) and constitutive-phospho-mimetic (Glu) mutations at Ser78 in a DNA-binding domain of BMAL1 also shortened the circadian period and abolished the rhythms, respectively. The mathematical modeling predicted that these constitutive-phospho-mimetic mutations weaken the DNA binding of the CLOCK-BMAL1 complex and that the nonphosphorylatable mutations inhibit the PER-dependent displacement (reduction of DNA-binding ability) of the CLOCK-BMAL1 complex from DNA. Biochemical experiments supported the importance of these phosphorylation sites for displacement of the complex in the PER2-dependent inhibition. Our results provide direct evidence that phosphorylation of CLOCK-Ser38/Ser42 and BMAL1-Ser78 plays a crucial role in the PER-dependent inhibition and the determination of the circadian period.-
dc.language영어-
dc.publisherNational Academy of Sciences-
dc.titlePhosphorylation of DNA-binding domains of CLOCK-BMAL1 complex for PER-dependent inhibition in circadian clock of mammalian cells-
dc.typeArticle-
dc.type.rimsART-
dc.identifier.wosid001243918100003-
dc.identifier.scopusid2-s2.0-85194887397-
dc.identifier.rimsid83223-
dc.contributor.affiliatedAuthorEui Min Jeong-
dc.contributor.affiliatedAuthorJae Kyoung Kim-
dc.identifier.doi10.1073/pnas.2316858121-
dc.identifier.bibliographicCitationProceedings of the National Academy of Sciences of the United States of America, v.121, no.23, pp.e2316858121-
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of America-
dc.citation.titleProceedings of the National Academy of Sciences of the United States of America-
dc.citation.volume121-
dc.citation.number23-
dc.citation.startPagee2316858121-
dc.description.journalClass1-
dc.description.journalClass1-
dc.description.isOpenAccessN-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.subject.keywordAuthorCRISPR-Cas9-
dc.subject.keywordAuthorDNA binding-
dc.subject.keywordAuthormathematical modeling-
dc.subject.keywordAuthorphosphorylation-
dc.subject.keywordAuthorcircadian rhythm-
Appears in Collections:
Pioneer Research Center for Mathematical and Computational Sciences(수리 및 계산과학 연구단) > Biomedical Mathematics Group(의생명 수학 그룹) > 1. Journal Papers (저널논문)
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