In cancer patients, treatment modalities like chemotherapy and radiation exert their anticancer effects by inducing DNA damage. The cancer cells can survive under genotoxic stress by inducing DNA damage response (DDR) or can undergo cell death. The process of autophagy is emerging as crucial regulator of cell survival during different stress conditions. Post translational modification through ubiquitin plays an essential role in DDR during genotoxic stress conditions. Ubiquitin ligases regulate autophagy and cell death pathways however their role during genotoxic stress conditions is not understood. In the current study we identified TRIM8, RING E3 Ligase, as a novel regulator of autophagy during DDR. TRIM8 regulates lysosomal biogenesis and autophagy flux. The turnover of TRIM8 is high and is stabilized during genotoxic stress conditions. TRIM8 regulated autophagy is essential for its cytoprotective role during genotoxic stress induced cell death. TRIM8 stabilizes the turnover of XIAP during genotoxic stress and forms complex with XIAP and caspase-3 to inhibit its activation in presence of etoposide. TRIM8 mediated autophagy promotes degradation of cleaved caspase-3 subunits. This study described TRIM8, as a novel regulator of DDR-autophagy crosstalk, which may play role in survival of cancer cells in presence of genotoxic agents.

在癌症患者中，化学疗法和放射疗法等治疗方式通过诱导DNA损伤发挥抗癌作用。通过诱导DNA损伤反应（DDR），癌细胞可以在遗传毒性胁迫下存活，或者可以发生细胞死亡。自噬过程正在成为不同应激条件下细胞存活的关键调节剂。在遗传毒性应激条件下，通过遍在蛋白进行的翻译后修饰在DDR中起着至关重要的作用。泛素连接酶调节自噬和细胞死亡途径，但是它们在遗传毒性应激条件下的作用尚不清楚。在本研究中，我们确定了TRI E8，RING E3连接酶是DDR期间自噬的新型调节剂。TRIM8调节溶酶体生物发生和自噬通量。TRIM8的周转率很高，并且在遗传毒性胁迫条件下稳定。TRIM8调控的自噬对其在遗传毒性应激诱导的细胞死亡过程中的细胞保护作用至关重要。TRIM8可在遗传毒性胁迫期间稳定XIAP的转换，并与XIAP和caspase-3形成复合物以抑制依托泊苷的存在。TRIM8介导的自噬促进裂解的caspase-3亚基的降解。这项研究将TRIM8描述为DDR自噬串扰的新型调节剂，在存在基因毒性剂的情况下，它可能在癌细胞的存活中发挥作用。