Néstor-Guillermo Progeria Syndrome (NGPS) is caused by the homozygous c.34G>A (p.Ala12Thr) mutation in the BANF1 gene. BANF1 encodes barrier-to-autointegration factor 1 (BAF), a small 89- amino-acid protein primarily located in the nucleus, with minor cytoplasmic presence. BAF’s functions are still under study, but it interacts with numerous partners, including non-specific DNA, LEM-domain proteins, lamin A/C, transcription factors, histones and other chromatin regulators. During interphase, BAF binds to lamin A/C and LEM-domain proteins, playing a critical role in the organization of the nuclear envelope. The p.Ala12Thr mutation does not impair its dimerization or the interaction with emerin and other LEM-domain proteins, but reduces its affinity to DNA and lamin A/C, leading to nuclear abnormalities.
Beyond its structural role, BAF is involved in DNA double strand breaks (DSB) repair. Upon DNA damage, a subpopulation of non-phosphorylated cytoplasmic BAF translocates to these DSB sites in the nucleus, serving as a scaffold for the recruitment of LEM-domain proteins, lamin C, cGAS and DNA repair machinery. BAF also directly binds and inhibits PARP1 and DNA-PKcs, modulating DSB repair. The p.Ala12Thr mutation in BAF causes a stronger binding to PARP1, inhibiting its activity in a similar way as in BAF overexpression and impairing the repair of oxidative DNA lesions. In contrast, the lack of wild-type BAF accelerates DSB repair via the non-homologous end-joining (NHEJ) cascade and reduces homologous recombination.
BAF also plays an essential role in chromosome segregation and nuclear envelope reassembly during mitosis. In S phase, nuclear BAF increases, facilitating lamin A migration to the nuclear envelope. When mitosis begins, BAF is phosphorylated by VRK1, loses its affinity to DNA, and detaches from chromatin, allowing nuclear envelope breakdown. In anaphase-telophase, PP2A dephosphorylates BAF, enabling chromatin binding and nuclear assembly. In parallel, BAF also associates with centromeric chromatin, recruiting envelope proteins, such as lamin A/C and emerin, and distant DNA to guide membrane formation.
Although the p.Ala12Thr mutation does not alter BAF’s 3D conformation or phosphorylation by VRK1, it reduces BAF’s binding to lamin A and DNA at centromeres, disrupting emerin and lamin localization during late mitosis. This impairs nuclear envelope integrity, facilitating re-ruptures. Finally, a recent study identified a novel role for BAF in regulating protein synthesis, demonstrated in both cell culture and Caenorhabditis elegans. This function is altered in the presence of the p.Ala12Thr mutation, leading to disrupted protein synthesis rate and fidelity. Nonetheless, the exact molecular mechanisms underlying the progeroid phenotype in NGPS remain incompletely understood.
BANF1