DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear. Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.

DNA-蛋白质交联 (DPC) 是威胁基因组完整性的剧毒 DNA 损伤。最近的研究结果强调 SPRTN 是一种专门的 DNA 依赖性金属蛋白酶，是 DPC 蛋白水解切割的核心参与者。以前的研究表明 SPRTN 去泛素化对其染色质结合和激活很重要。然而，SPRTN 去泛素化的调控和后果仍不清楚。在这里我们报告说，响应 DPC 诱导，去泛素化酶 VCPIP1/VCIP135 被 ATM/ATR 磷酸化和激活。反过来，VCPIP1 使 SPRTN 去泛素化并促进其染色质重定位。SPRTN 的去泛素化是其后续乙酰化所必需的，这会促进 SPRTN 重新定位到染色质损伤部位。此外，Vcpip1基因敲除小鼠容易出现基因组不稳定和过早衰老。我们提出了一个模型，其中两个连续的翻译后修饰 (PTM) 调节 SPRTN 染色质的可及性，以修复 DPC 并保持基因组稳定性和健康的寿命。