Project description:Creatine kinase (CK) is an essential metabolic enzyme mediating creatine/phosphocreatine interconversion and shuttle to replenish ATP for energy needs. Ablation of CK causes deficiency in energy supply that eventually results in reduced muscle burst activity and neurological disorders in mice. Besides the well-established role of CK in energy-buffering, the mechanism underlying non-metabolic function of CK is poorly understood. Here we demonstrate that creatine kinase brain-type (CKB) may function as a protein kinase to regulate BCAR1 Y327 phosphorylation that enhances the association between BCAR1 and RBBP4. Then the complex of BCAR1 and RPPB4 binds to the promoter region of DNA damage repair gene RAD51 and activates its transcription by modulating histone H4K16 acetylation to ultimately promote DNA damage repair. These findings reveal the possible role of CKB independently of its metabolic function and depict the potential pathway of CKB-BCAR1-RBBP4 operating in DNA damage repair.
Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.
Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.
Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.
Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.
Project description:Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation.
Project description:The eukaryotic RNA processing factor Y14 participates in double-strand break (DSB) repair via its RNA-dependent interaction with the non-homologous end-joining (NHEJ) complex. We identified the long non-coding RNA HOTAIRM1 as a candidate that mediates this interaction. HOTAIRM1 localized to DNA damage sites induced by ionizing radiation. Depletion of HOTAIRM1 delayed the recruitment of DNA damage response and repair factors to DNA lesions and reduced DNA repair efficiency. Identification of the HOTAIRM1 interactome revealed a large set of RNA processing factors including mRNA surveillance factors. The surveillance factors Upf1 and SMG6 localized to DNA damage sites in a HOTAIRM1-dependent manner. Depletion of Upf1 or SMG6 increased the level of DSB-induced non-coding transcripts at damaged sites, indicating a pivotal role for Upf1/SMG6-mediated RNA degradation in DNA repair. We conclude that HOTAIRM1 serves as an assembly scaffold for both DNA repair and RNA processing factors that act in concert to repair DSBs.