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Supplementary Figures S1-S14. p53 levels in p53 knockdown GBM cells (S1); TMZR3 cells obtained from a p53 deficient background display increased ploidy (S2); H2AX activation in temozolomide treated parental and TMZR3 GBM cells (S3); In-cell Host cell reactivation (HCR) assays used to assess the MGMT and MMR repair capacity of GBM cells (S4); MSH6 and MSH2 levels in MSH6 and MSH2 knockdown GBM cells (S5); Cell cycle profiles and quantitation of cell cycle changes in TMZ-treated MSH6 knockdown cells two cell cycle times post-TMZ treatment (S6); Cell cycle profiles and quantitation of cell cycle changes in TMZ-treated MSH2 knockdown cells two cell cycle times post-TMZ treatment (S7); Minor decreases in MSH2 levels correlate with acquired TMZ resistance in LN229 and A172 GBM cells (S8); Effects of MSH6 or MSH2 knockdown on the protein level of its dimerization partner (S9); Msh2 knockdown in GL261 glioblastoma cells (S10); Moderate decreases in Msh2 confer a growth advantage to GL261 GBM cells after TMZ, but not BCNU, exposure in vitro (S11); Distribution of patient survival in TMZ treated TCGA GBM patients and effects of MSH2 transcript levels on the survival of TMZ treated patients in the 95th percentile for patient survival after TMZ therapy (S12); Overall survival of GBM patients stratified by MSH3, MLH1 and PMS2 tumor transcript levels (S13); PMS2 transcript levels correlate with increased chromosome 7 copy number (S14).

Supplementary Tables S1-S2. O6-methylguanine adducts levels in parental and TMZR3 GBM cells 3 hours post-TMZ exposure (S1); shRNA constructs used in this study (S2).

Supplementary Methods and Discussion. Description of additional methods and procedures used in the study. Also includes Supplementary References.

Age‐related macular degeneration (AMD) is a multifactorial disease, which is characterized by loss of central vision, affecting one in three people by the age of 75. The Y402H polymorphism in the complement factor H (CFH) gene significantly increases the risk of AMD. We show that Y402H‐AMD‐patient‐specific retinal pigment epithelium (RPE) cells are characterized by a significant reduction in the number of melanosomes, an increased number of swollen lysosome‐like‐vesicles with fragile membranes, Cathepsin D leakage into drusen‐like deposits and reduced lysosomal function. The turnover of C3 is increased significantly in high‐risk RPE cells, resulting in higher internalization and deposition of the terminal complement complex C5b‐9 at the lysosomes. Inhibition of C3 processing via the compstatin analogue Cp40 reverses the disease phenotypes by relieving the lysosomes of their overburden and restoring their function. These findings suggest that modulation of the complement system represents a useful therapeutic approach for AMD patients associated with complement dysregulation., Schematic presentation of autophagy‐lysosomal pathway dysfunction in Y402H‐AMD RPE cells and the impact of Cp40 in restoring the lysosomal function.