3-21 PAXX is essential for end-joining in XLF-deficient mice

报告题目: PAXX is essential for end-joining in XLF-deficient mice

报 告  人: 刘向宇博士(Associate Research Scientist,Department of Pathology, Columbia University)

报告时间:3月21日  上午9:30


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Non-homologous end-joining (NHEJ) is the most prominent DNA double strand break (DSB) repair pathway in mammalian cells. PAXX is the newest NHEJ factor, which shares structural similarity with known NHEJ factors—XRCC4 and XLF. Here we report that PAXX is dispensable for physiological NHEJ in wild-type mice. Yet Paxx-/- mice require XLF and Xlf-/- mice require PAXX for end-ligation. As such, Xlf-/-Paxx-/- mice display severe genomic instability and neuronal apoptosis, which eventually lead to embryonic lethality. Despite their structural similarities, only Xlf-/- cells, but not Paxx-/- cells require ATM/DNA-PK kinase activity for end-ligation. Mechanistically, PAXX promotes the accumulation of KU at DSBs, while XLF enhances LIG4 recruitment without affecting KU dynamics at DNA breaks in vivo. Together these findings identify the molecular functions of PAXX in KU accumulation at DNA ends and reveal distinct, yet critically complementary functions of PAXX and XLF during NHEJ.



刘向宇博士2002年至2010年就读于北京大学医学部基础医学专业(八年制本博连读)生物化学与分子生物学系,获得博士学位后前往美国纽约哥伦比亚大学医学院肿瘤基因研究所(Institute for Cancer Genetics)从事博士后研究工作。目前专业技术职位为助理研究科学家(Associate Research Scientist),从事研究方向主要集中于:DNA损伤后的非同源末端连接(Non-homologous end joining, NHEJ),同源重组修复(Homologous recombination, HR)以及替代性末端连接(Alternative end joining, A-EJ)的机制研究,DNA断端切除(DNA end resection)引起的染色质异位而导致的原癌基因的转录激活,基因组稳定性及癌症的发生发展机制,抑癌基因p53的作用机制,CRISPR-Cas9基因编辑动物模型的建立等。这些工作分别以研究文章和综述的形式发表在国际著名学术刊物PNAS,Mol Cell,Nat Commun,Oncotarget,JCB,Cancer Cell等。