Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair

DNA damage isa double-edged sword for cancer cells. On the one hand, DNA damage-induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Under-standing the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that iso-prenylcysteine carboxylmethyltransferase (ICMT), a posttrans-lational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition trans -forms the cancer cells into a BRCA-like state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage-inducing agents.

Automated summary

DNA damage has a dual impact on cancer cells: inducing genomic instability to promote cancer development while compromising proliferation and survival. Inhibiting ICMT reduces MAPK signaling activity, impairs DNA damage repair machinery, leading to cell cycle arrest and apoptosis in cancer cells. ICMT inhibition transforms cancer cells into a BRCA-like state, sensitizing them to PARP inhibitor and other DNA-damaging agents, particularly in anchorage-independent or in vivo conditions.