Centre de Recherche du Centre Hospitalier de l'Universite de Montréal (CRCHUM), et Institut du cancer de Montréal, Montreal, QC, Canada.
Centre de Recherche du Centre Hospitalier de l'Universite de Montréal (CRCHUM), et Institut du cancer de Montréal, Montreal, QC, Canada ; Département de Radiologie, Radio-Oncologie et Médicine Nucléaire, Université de Montréal Montreal, QC, Canada.
Front Genet. 2015 Mar 12;6:94. doi: 10.3389/fgene.2015.00094. eCollection 2015.
The DNA damage response (DDR) is an evolutionarily conserved signaling cascade that senses and responds to double-strand DNA breaks by organizing downstream cellular events, ranging from appropriate DNA repair to cell cycle checkpoints. In higher organisms, the DDR prevents neoplastic transformation by directly protecting the information contained in the genome and by regulating cell fate decisions, like apoptosis and senescence, to ensure the removal of severely damaged cells. In addition to these well-studied cell-autonomous effects, emerging evidence now shows that the DDR signaling cascade can also function in a paracrine manner, thus influencing the biology of the surrounding cellular microenvironment. In this context, the DDR plays an emerging role in shaping the damaged tumor microenvironment through the regulation of tissue repair and local immune responses, thereby providing a promising avenue for novel therapeutic interventions. Additionally, while DDR-mediated extracellular signals can convey information to surrounding, undamaged cells, they can also feedback onto DNA-damaged cells to reinforce selected signaling pathways. Overall, these extracellular DDR signals can be subdivided into two time-specific waves: a rapid bystander effect occurring within a few hours of DNA damage; and a late, delayed, senescence-associated secretory phenotype generally requiring multiple days to establish. Here, we highlight and discuss examples of rapid and late DDR-mediated extracellular alarm signals.
DNA 损伤反应 (DDR) 是一种进化上保守的信号级联反应，通过组织下游的细胞事件来感知和应对双链 DNA 断裂，这些事件范围从适当的 DNA 修复到细胞周期检查点。在高等生物中，DDR 通过直接保护基因组中包含的信息以及通过调节细胞命运决定（如细胞凋亡和衰老）来防止肿瘤转化，以确保去除严重受损的细胞。除了这些研究得很好的细胞自主效应外，新出现的证据表明，DDR 信号级联也可以以旁分泌的方式发挥作用，从而影响周围细胞微环境的生物学特性。在这种情况下，DDR 通过调节组织修复和局部免疫反应，在塑造受损的肿瘤微环境方面发挥着新兴作用，从而为新的治疗干预提供了有前途的途径。此外，虽然 DDR 介导的细胞外信号可以将信息传递给周围未受损的细胞，但它们也可以反馈到 DNA 损伤的细胞上，以加强选定的信号通路。总的来说，这些细胞外 DDR 信号可以分为两个特定时间的波：在 DNA 损伤后几小时内发生的快速旁观者效应；以及通常需要数天才能建立的晚期、延迟的衰老相关分泌表型。在这里，我们强调并讨论了快速和晚期 DDR 介导的细胞外警报信号的例子。
