cGAS guards against chromosome end-to-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.

Role of the stability of deoxyribonucleoside triphosphate pool in the development and progression of tumors / 肿瘤研究与临床

The stability of deoxyribonucleoside triphosphate (dNTP) pool is essential for the normal synthesis of nuclear and mitochondrial DNA. The lack or excess of any dNTP may cause DNA damage and genomic instability, and increase mutation rate. Present studies have confirmed that the instability of dNTP pool is closely related to a variety of tumorigenesis. In addition, dNTP pool is involved in the development of tumor via multiple pathways, while the mechanisms of tumors caused by the instability of dNTP are complicated. This paper discusses the relationship between the stability of dNTP pool and DNA damage repair to provide a theoretical basis for early diagnosis and targeted treatment of tumors.

Functional research advances of the protection of alpha crystallin to the lens transparency / 中华实验眼科杂志

α-Crytallin,composed of two menbers of the small heat shock protein,is the major component of the cytoplasm in lens.α-Crytallin not only possesses chaperone-like activity,but also plays important roles in regulation of cell cycle,enhancing genome stability and prevention of the stress-induced apoptosis.The gene mutation associated with α-crytallin is a common cause of hereditary cataract,which is the major cause of childhood blindness.Whereas various changes of the α-crytallin can result in the most common cause of blindness in the world—age-related cataract.Understanding of the function of α-crytallin helps to comprehend the development of lens and how the lens maintain its normal function,and to provide a theoretical basis for the prevention and treatment of the cataract related to the malfunction of α-crytallin.The genetic mapping and mechanism of cataract and the function of α-crytallin are summarized here.