DNA损伤反应（DDR）在癌症预防和治疗中发挥着至关重要的作用。多聚(ADP-核糖)聚合酶1（PARP1）作为主要调节因子在DDR中介导多重信号转导。揭示PARP1的调节因素有助于更全面地了解肿瘤发生和治疗策略。在这里，我们揭示了MARVELD1作为DDR的介质，在执行早期事件和维持基因组稳定性方面发挥作用。机械上，PARP1在D102、D118和D130处PARylates MARVELD1，反过来，MARVELD1通过增强NAA50介导的乙酰化来稳定PARP1，从而形成正向反馈循环。MARVELD1敲除小鼠及其胚胎成纤维细胞表现出基因组不稳定性和PARP1的寿命缩短。此外，MARVELD1与PARP1合作有助于抵抗基因毒性药物并在结直肠癌（CRC）PDX模型中破坏PARP抑制剂（PARPi）效果。总体而言，我们的结果强调了MARVELD1在基于DDR的治疗抵抗中与PARP1之间的联系，并为PARPi的临床肿瘤治疗提供了新的见解。©2023。作者（们）。

The DNA damage response (DDR) plays crucial roles in cancer prevention and therapy. Poly(ADP-ribose) polymerase 1 (PARP1) mediates multiple signal transduction in the DDR as a master regulator. Uncovering the regulatory factors of PARP1 contributes to a more comprehensive view of tumorigenesis and treatment strategies. Here, we reveal that MARVELD1 acts as a mediator of DDR to perform early events and maintain genome stability. Mechanistically, PARP1 PARylates MARVELD1 at D102, D118 and D130, and in turn, MARVELD1 stabilizes PARP1 by enhancing NAA50-mediated acetylation, thus forming a positive feedback loop. MARVELD1 knockout mice and their embryo fibroblasts exhibit genomic instability and shorter half-life of PARP1. Moreover, MARVELD1 partnering with PARP1 facilitates resistance to genotoxic drugs and disrupts PARP inhibitor (PARPi) effect in PDX model of colorectal cancer (CRC). Overall, our results underline the link between MARVELD1 and PARP1 in therapeutic resistance based on DDR and provide new insights for clinical tumor therapy of PARPi.© 2023. The Author(s).