基因组DNA的损伤会激活细胞内的损伤应答(DDR)通路。复制性衰老、应激诱导的衰老、以及原癌基因激活的衰老屏障等细胞衰老模型中都有明显的DNA损伤和DDR。衰老相关的分泌表型(SASP)是新近发现的细胞衰老关键分子特征之一。NF-kappaB作为调控诸多炎性分泌基因表达水平的核心转录因子，在SASP的发生和发展过程中起着重要作用。通过前期的功能筛选实验，我们找到一个具有FHA结构域的炎症相关蛋白TIFA，可以在DNA损伤条件下入核并明显富集于染色质上。初步实验发现TIFA可以通过促进DNA损伤时NEMO的泛素化修饰，诱导NF-kappaB的激活以及衰老相关分泌表型。我们相信深入探索以TIFA为核心节点的、能在DNA损伤条件下转导损伤信号到NF-kappaB的信号通路的分子机制和生物学功能，对于我们理解SASP的分子机理并通过SASP来调控衰老进程、肿瘤发生和转移有非常重要的意义。

Challenges to the genome integrity would elicit DNA damage response (DDR). DNA damages and DDR events, including the special irreparable telomeric DNA damage could be detected in replicative and stress-induced cellular senescence, as well as in over-activated oncogene-associated senescence barrier models. Among the arrays of distinctive phenotypesand biomarkers in cellular senescence, there was a burst of nvestigations on secretory factors associated with inflammation and malignancy, which were designed as "senescence-associated secretory phenotype" (SASP) owing to their induction by replicative or stress-triggered senescence. These myriad factors, including panels of cytokines, chemokines and interferons, contribute to aging process in an autocrine, paracrine or endocrine fashion via their collaborations with DNA damage response. Nuclear factor-kappaB (NF-kappaB) is the master regulators responsible for transcriptional activation of inflammation machinery, and subunit of this family was identified as major transcription factor accumulated on chromatin of senescent cells. However, the molecular mechanisms linking nuclear DDR and cytoplasmic IKK (Inhibitor of Nuclear Factor kappa-B Kinase) activation in the context of cellular senescence remains not fully understood. In our pilot experiments, a FHA (Forkhead-associated) domain-containing protein TIFA (TRAF-interacting protein with an FHA domain) without any previously identified roles in DDR-elicited NF-kappaB activation, was observed to be translocated into nucleus and accumulated on damaged chromatin following genotoxic stress. Biochemical and molecular biological experiments further revealed that under DNA damage conditions TIFA promoted ubiquitination of NEMO (NF-kappaB Essential Modulator), which was a key transducer of DDR signals to cytoplasmic IKK complex assembly, and that TIFA could induce NF-kappaB activation and SASP subsequently. We believe the elucidation of mechanistic details for TIFA-mediated transduction of DDR signals to NF-kappaB activation and TIFA-elicited SASP would not only contribute to the molecular dissection of aging and senescence barrier in caners, but also provide novel pharmatheutical target for taking advantage of SASP in cancer development and metastasis.