PHF6 drives satellite DNA chromatin remodeling for resolution of replicative stress-induced DNA damage
The Plant Homeodomain 6 gene (PHF6) encodes a nucleolar and chromatin-associated factor with proposed roles in chromatin remodeling and transcription regulation. Germline mutations in PHF6 are causative of Börjesson-Forsmann-Lehman syndrome, while somatic loss-of-function genetic alterations support a tumor suppressor role in leukemia. Yet, the specific molecular function and mechanisms of PHF6 remain poorly understood. Here we show that PHF6 associates with chromatin remodeling and DNA repair factors in multiprotein complexes at satellite repeat heterochromatin regions and facilitates double strand break repair in the context of replicative stress-induced DNA damage. Mechanistically, PHF6 localizes to sites of DNA damage and its inactivation impairs the resolution of DNA breaks promoting the accumulation of single and double-stranded DNA lesions. In addition, PHF6 associates with difficult to replicate Histone H3 lysine 9 trimethylation (H3K9me3)-marked heterochromatin at satellite DNA regions, prevents accelerated replication fork dynamics and is required to maintain genomic integrity at fragile sites. In all, these results demonstrate a critical role for PHF6-containing chromatin-remodeling complexes in homologous recombination DNA-repair and in the resolution of satellite DNA-associated replicative stress. Overall design: Examination of PHF6 chromatin binding in T-acute lymphoblastic leukemia cells