<p>DNA damage activates the DNA damage response (DDR) machinery. However, aging impairs DDR in neurons, thereby increasing susceptibility to neurodegenerative diseases, such as Huntington’s disease (HD). The mutant huntingtin (mHTT) protein interferes with DNA repair, leading to DNA lesions and a feedback loop of cellular stress that accelerates neurodegeneration. Although the individual roles of FBXW7, ATM, and checkpoint kinase (CHK) are well-known in DDR, their combined roles in HD remain unclear. In this study, we investigated the FBXW7-mediated CHK2 pathway in HD, in which mHTT levels increase, whereas wild-type (WT) HTT levels decrease. HD cells containing mHTT or expanded polyQ-HTT were more prone to DNA damage than cells containing wtHTT or normal-length polyQ, demonstrating the increased vulnerability of HD neurons. Downregulating the expression of FBXW7 reduces susceptibility to DNA damage and promotes cellular stability. Additionally, FBXW7 specifically prevented CHK2 degradation, but not CHK1 degradation. This suggests a selective role in DDR regulation. Thus, the FBXW7-CHK2 pathway may alleviate DNA damage in HD by supporting DDR and inducing cell cycle arrest. The intricate relationship between DDR and HTT is fundamental to the pathophysiology of HD. Elucidating these mechanisms could facilitate the development of new therapeutic strategies that enhance DNA repair or correct DDR dysfunction, thereby slowing disease progression or delaying symptom onset. Understanding this pathway may provide insights into the targeting of DNA repair defects in HD and related neurodegenerative disorders.</p>