NS and PML-IV protect both ALT and TA⁺ cells from TRF2-DN–induced telomere damage. Overexpression of NS or PML-IV protects U2OS cells (A) and HeLa cells (B) from TRF2-DN–induced TIF without affecting the total number of TRF1-GFP foci. (C) Compared with wild-type NS (NS-WT), the nucleoplasmic mutant of NS (NSdB) shows a stronger or similar activity in reducing TRF2-DN–induced TIF in U2OS and HeLa cells, respectively. (D) PML-IV can rescue the NS-KD–induced telomere (TIF) and nontelomeric (IDF) damage in U2OS and HeLa cells. (E) A proposed model for the NS function in protecting ALT and TA⁺ cells from telomere damage via the recruitment of RAD51-bound PML-IV to SUMOylated TRF1. Bars, 5 µm.