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1.
Oncogene ; 42(13): 967-979, 2023 03.
Article in English | MEDLINE | ID: mdl-36725890

ABSTRACT

Accumulating evidence indicates a correlation between circadian dysfunction and genomic instability. However, whether the circadian machinery directly regulates DNA damage repair, especially in double-strand breaks (DSBs), remains poorly understood. Here, we report that in response to DSBs, BMAL1 is activated by ATM-mediated phosphorylation at S183. Phosphorylated BMAL1 is then localized to DNA damage sites, where it facilitates acetylase CLOCK to load in the chromatin, regulating the acetylation of histone H4 (H4Ac) at DSB sites. In this way, the BMAL1-CLOCK-H4Ac axis promotes the DNA end-resection to generate single-stranded DNA (ssDNA) and the subsequent homologous recombination (HR). BMAL1 deficient cells display defective HR, accumulation of unrepaired DSBs and genome instability. Accordingly, depletion of BMAL1 significantly enhances the sensitivity of adrenocortical carcinoma (ACC) to DNA damage-based therapy in vitro and in vivo. These findings uncover non-canonical function of BMAL1 and CLOCK in HR-mediated DSB repair, which may have an implication in cancer therapeutics.


Subject(s)
DNA Breaks, Double-Stranded , Neoplasms , Humans , ARNTL Transcription Factors/genetics , DNA , DNA End-Joining Repair , DNA Repair , Drug Resistance, Neoplasm/genetics , Homologous Recombination , Neoplasms/drug therapy , Neoplasms/genetics , CLOCK Proteins/metabolism
2.
Sci China Life Sci ; 65(12): 2505-2516, 2022 12.
Article in English | MEDLINE | ID: mdl-35661964

ABSTRACT

TERC is the RNA component of telomerase, and provides a template for TERT to synthesize telomere repeats at chromosome ends. Increasing evidence has revealed that TERC is involved in other biological processes beyond telomerase. Here, we found that the expression level of TERC is negatively correlated with PD-L1 and that ectopic expression of TERC but not TERT in ALT cells significantly inhibits PD-L1, suggesting that TERC suppresses PD-L1 expression in a telomerase-independent manner. Mechanistically, instead of regulating PD-L1 mRNA directly, TERC accelerates PD-L1 mRNA degradation by inhibiting the expression of HuR, which binds to the 3'UTR of PD-L1 mRNA and maintains its stability. We also found that the small molecule AS1842856, a FoxO1 inhibitor, promotes TERC expression and reverses the PD-L1 upregulation caused by chemotherapy, providing a potential combination cancer therapy that avoids cancer immune escape during chemotherapy.


Subject(s)
Neoplasms , Telomerase , Humans , Telomerase/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , RNA/metabolism , Telomere/metabolism , Neoplasms/genetics , Neoplasms/metabolism , RNA, Messenger/genetics
3.
Protein Cell ; 13(1): 47-64, 2022 01.
Article in English | MEDLINE | ID: mdl-34676498

ABSTRACT

As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.


Subject(s)
Cellular Senescence , Chromosomes, Human/metabolism , Genomic Instability , Mitosis , Nucleotidyltransferases/metabolism , Telomere/metabolism , Chromosomes, Human/genetics , HeLa Cells , Humans , Nucleotidyltransferases/genetics , Telomere/genetics
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