课题基金 / 基金详情

Non-canonical cGAS signaling in DNA damage response

Non-canonical cGAS signaling in DNA damage response
DNA 损伤反应中的非典型 cGAS 信号传导
批准号:
10307611
负责人:
Nagaraj Kerur
金额:
$48.63万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-12-05 至 2025-11-30

项目摘要

项目成果

Nagaraj Kerur的其他基金

相似基金

相关文献

中文摘要
翻译
总结
英文摘要
SUMMARY The vertebrate innate immunity relies upon a complex set of cytosolic pattern recognition receptors (PRR) to detect pathogen-derived, evolutionarily conserved molecules such as DNA. The sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) activates the enzymatic synthesis of cyclic guanosine monophosphate- adenosine monophosphate (cGAMP), a cyclic dinucleotide (CDN) second messenger. cGAMP signals via its high affinity receptor protein STING, which subsequently recruits TANK-binding kinase 1 (TBK1) and interferon (IFN) regulatory factor 3 (IRF3) to stimulate the induction of type I IFNs. Although originally identified as a cytosolic sensor of foreign DNA, cGAS is also recruited to and activated by fragments of chromatin from damaged genomic DNA in the cytosol or micronuclei. Multiple convergent studies have recently highlighted the significance of cGAS in the DNA damage–induced inflammatory response and its implications for cellular senescence, tumorigenesis, and metastasis. Nothing, however, is known about whether cGAS activation in these contexts directly contributes to the maintenance of genome integrity. Recent studies in our laboratory have discovered that cGAS/cGAMP signaling triggers DNA damage response (DDR), independently of its well-characterized type I interferon pathway. These studies revealed that cGAMP-induced DDR activates cell cycle checkpoint responses that lead to G1 arrest and subsequent suppression of homology directed repair (HDR) of double-strand DNA breaks (DSB) in CRISPR/Cas9-edited mouse embryos and human and mouse cells. Interestingly, the cGAMP-induced DDR was also demonstrable in invertebrate species (oysters and starlet sea anemone) lacking interferon-based immune system, suggesting that the DNA damage surveillance mechanism of cGAMP predates its more well- known IFN-mediated immune function. The studies proposed here aim to advance these novel findings by elucidating the molecular mechanism of cGAS/cGAMP-induced DDR induction via three thematically integrated, yet independent Aims: (1) Decipher the critical signaling pathways involved in cGAMP-induced ATM activation; (2) Define the molecular mechanism of cGAS-cGAMP-induced suppression of HDR; and (3) Elucidate whether cGAMP-induced DDR potentiates the cGAS-initiated innate immunity. In summary, this work will illuminate novel aspects of the molecular and biochemical basis of cGAMP-induced activation of the apical DDR signaling kinase ATM, and increase understanding of the relationship between cGAMP-induced DDR signaling and the traditional immune function of cGAS.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Non-canonical cGAS signaling in DNA damage response
  • 批准号:
    10287373
  • 项目类别:
  • 资助金额:
    $34.27万
  • 财政年份:
    2019
  • 负责人:
    Nagaraj Kerur
  • 依托单位:
Telomerase in choroidal neovascularization
  • 批准号:
    9808042
  • 项目类别:
  • 资助金额:
    $24.23万
  • 财政年份:
    2019
  • 负责人:
    Nagaraj Kerur
  • 依托单位:
Telomerase in choroidal neovascularization
  • 批准号:
    10378972
  • 项目类别:
  • 资助金额:
    $14.26万
  • 财政年份:
    2019
  • 负责人:
    Nagaraj Kerur
  • 依托单位:
Non-canonical cGAS signaling in DNA damage response
  • 批准号:
    10064992
  • 项目类别:
  • 资助金额:
    $18.55万
  • 财政年份:
    2019
  • 负责人:
    Nagaraj Kerur
  • 依托单位:
海外基金