Phosphoregulated SMCR8-FIP200 interaction connects the ALS/FTD-linked C9orf72 complex to autophagy initiation and mitochondrial quality control

Hexanucleotide (GGGGCC) repeat expansions in the non-coding region of C9ORF72 are a major genetic cause of ALS/FTD and reduce C9orf72-SMCR8-WDR41 complex levels, but how this contributes to autophagy-lysosome dysfunction and previously reported mitochondrial quality-control defects in C9ORF72-ALS/FTD remains unclear. Here we identify a direct interaction between SMCR8 and the FIP200 subunit of the ULK1/2 autophagy […]

Therapy-associated mutagenesis at CTCF binding sites is shaped by chromatin context and DNA repair capacity

Genotoxic cancer therapies introduce DNA damage that can be fixed as somatic mutations in surviving tumor cells. However, the impact of therapy-associated mutagenesis on regulatory elements remains unclear. CTCF binding sites (CBS) are chromatin architectural elements that exhibit recurrent localized mutation enrichment in cancer genomes. We asked whether treatment exposure is associated with increased mutagenesis […]

Dissecting polycomb complexes for enhanced fetal hemoglobin production

Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and beta-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) […]

Dissecting polycomb complexes for enhanced fetal hemoglobin production

Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and beta-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) […]

Therapy-associated mutagenesis at CTCF binding sites is shaped by chromatin context and DNA repair capacity

Genotoxic cancer therapies introduce DNA damage that can be fixed as somatic mutations in surviving tumor cells. However, the impact of therapy-associated mutagenesis on regulatory elements remains unclear. CTCF binding sites (CBS) are chromatin architectural elements that exhibit recurrent localized mutation enrichment in cancer genomes. We asked whether treatment exposure is associated with increased mutagenesis […]

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