cGAS guards against chromosome endto-end fusions during mitosis and facilitates replicative senescence

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.

Therapeutic potential of C1632 by inhibition of SARS-CoV-2 replication and viral-induced inflammation through upregulating let-7

Dear Editor,The COVID-19 pandemic caused by SARS-CoV-2 has led to acute respiratory distress syndrome(ARDS)with a high rate of death.An excessive inflammatory response,caused by virus infection,is associated with severe clinical manifestations that may lead to death of patients.1 Therefore,the blockage of virus replication and suppression of hyper-inflammatory response are beneficial for COVID-19 treatment.However,the drug targeting both virus and hyper-inflammation,as far as we know,is not available yet.

TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR

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 m RNA directly,TERC accelerates PD-L1 m RNA degradation by inhibiting the expression of Hu R,which binds to the 3′UTR of PD-L1 m RNA and maintains its stability.We also found that the small molecule AS1842856,a Fox O1 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.