Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death.,The EMBO Journal

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Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-09-23 , DOI: 10.15252/embj.2019102718
Hui Jiang ₁ , Xiaoyu Xue _{2,

3} , Swarupa Panda ₁ , Ajinkya Kawale ₂ , Richard M Hooy ₄ , Fengshan Liang ₂ , Jungsan Sohn ₄ , Patrick Sung _{2,

5} , Nelson O Gekara _{1,

6}

Affiliation

DNA repair via homologous recombination (HR) is indispensable for genome integrity and cell survival but if unrestrained can result in undesired chromosomal rearrangements. The regulatory mechanisms of HR are not fully understood. Cyclic GMP-AMP synthase (cGAS) is best known as a cytosolic innate immune sensor critical for the outcome of infections, inflammatory diseases, and cancer. Here, we report that cGAS is primarily a chromatin-bound protein that inhibits DNA repair by HR, thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress. This function is independent of the canonical STING-dependent innate immune activation and is physiologically relevant for irradiation-induced depletion of bone marrow cells in mice. Mechanistically, we demonstrate that inhibition of HR repair by cGAS is linked to its ability to self-oligomerize, causing compaction of bound template dsDNA into a higher-ordered state less amenable to strand invasion by RAD51-coated ssDNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability-associated disorders including cancer.

中文翻译：

染色质结合的cGAS是DNA修复的抑制剂，因此会加速基因组不稳定和细胞死亡。

通过同源重组（HR）进行DNA修复对于基因组完整性和细胞存活是必不可少的，但是如果不受限制，则会导致不希望的染色体重排。人力资源的调节机制尚未完全了解。环状GMP-AMP合酶（cGAS）是众所周知的胞质先天免疫传感器，对感染，炎性疾病和癌症的后果至关重要。在这里，我们报道cGAS主要是一种染色质结合蛋白，可抑制HR修复DNA，从而在基因组应激条件下加速基因组不稳定，微核生成和细胞死亡。此功能独立于规范的STING依赖的先天免疫激活，并且在生理上与辐射诱导的小鼠骨髓细胞耗竭有关。机械上，我们证明了cGAS对HR修复的抑制作用与其自身寡聚化能力有关，从而使结合的模板dsDNA压实成较高阶的状态，从而不易受到RAD51包覆的ssDNA细丝的链入侵。cGAS的这种以前未知的作用对于理解其参与与基因组不稳定性相关的疾病（包括癌症）具有意义。

更新日期：2020-03-19

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