解螺旋酶DDX11通过调节CtIP-MRN复合体对DSBs末端剪切促进同源重组修复的机制研究

同源重组(HR)是DNA双链断裂（DSBs）修复的主要通路之一，且为无错修复。断裂末端的单链剪切形成3´单链DNA(ssDNA)是HR修复的关键起始步骤，其机制还有待进一步明确。我们前期预研发现，解螺旋酶DDX11在放射诱发DNA损伤后可被募集到DNA损伤位点，与HR修复通路重要调节蛋白CtIP、MRE11存在相互作用，敲低DDX11导致HR修复抑制、细胞放射敏感性增加。本课题拟在前期预研基础上，探究DDX11参与调控DNA双链断裂HR修复的功能及机制，重点研究：DDX11募集到DNA损伤位点的分子机制、与已知HR修复蛋白的相互调节作用、DDX11的解螺旋酶活性在DNA双链断裂末端单链剪切形成3´ssDNA中的作用，以揭示DDX11在放射所致DNA损伤修复中的新功能，同时，阐明解螺旋酶协同CtIP-MRN复合物促进DSBs末端单链剪切作用，深入解析HR修复通路机制。

Homologous recombination(HR) is described as an error-free process and is one of the two major pathways to repair DNA double strand breaks(DSB).DNA end resection,which cuts the DSB ends and generates 3′ single-stranded DNA (ssDNA),is an essential step of HR,but its mechanism is still unclear. Previous studies in our lab showed that: 1) DDX11 was recruited to DNA damage site in response to irradition induced DNA damage;2) DDX11 interacted with the DNA damage repair associated proteins CtIP and MRE11;3)Knocking down of DDX11 attenuated HR repair and increased the radiation sensitivity of cancer cells.Accordingly, we presumed that DDX11 plays an important role in DNA damage repair.Therefore, We intend to do a systematic research on the effects and molecular mechanisms of DDX11 in HR repair: 1)the mechanisms of DDX11 recuriment to DNA damage sites;2) the function of its interaction with HR-associated proteins;3) the role of its helicase activity in DSBs end resection. Our study will reveal novel functions of DDX11 in DNA damage repair as well as discover novel mechanisms in the regulation of HR DNA end resection.