Abstract
Barrier-to-Autointegration Factor 1 (Banf1/BAF) is a critical component of the nuclear envelope and is involved in the maintenance of chromatin structure and genome stability. Banf1 is a small DNA binding protein that is conserved amongst multicellular eukaryotes. Banf1 functions as a dimer, and binds non-specifically to the phosphate backbone of DNA, compacting the DNA in a looping process. The loss of Banf1 results in loss of nuclear envelope integrity and aberrant chromatin organisation. Significantly, mutations in Banf1 are associated with the severe premature ageing syndrome, Néstor–Guillermo Progeria Syndrome. Previously, rare human variants of Banf1 have been identified, however the impact of these variants on Banf1 function has not been explored. Here, using in silico modelling, biophysical and cell-based approaches, we investigate the effect of rare human variants on Banf1 structure and function. We show that these variants do not significantly alter the secondary structure of Banf1, but several single amino acid variants in the N- and C-terminus of Banf1 impact upon the DNA binding ability of Banf1, without altering Banf1 localisation or nuclear integrity. The functional characterisation of these variants provides further insight into Banf1 structure and function and may aid future studies examining the potential impact of Banf1 function on nuclear structure and human health.
Highlights
The separation of the genome from the cytoplasm is a defining characteristic of eukaryotic cells (Alvarado-Kristensson and Rossello, 2019)
Among the 7 Banf1 mutations examined, R75W and N70T are within the DNA-binding region of the pseudo helix-hairpin-helix region, and H7Y is adjacent to the N-terminal DNA binding region, suggesting that these mutations may affect the binding of Banf1 to DNA
Highlighting the importance of nuclear envelope proteins, mutations in genes encoding several of these proteins are associated with human diseases including Emerin (Emery-Dreifuss Muscular Dystrophy), Lamin A/C (Hutchinson-Gilford progeria syndrome) and Banf1 (Nestor-Guillermo progeria syndrome)
Summary
The separation of the genome from the cytoplasm is a defining characteristic of eukaryotic cells (Alvarado-Kristensson and Rossello, 2019). For many years the nuclear envelope was viewed as a physical barrier to protect the cellular genetic material from damage and degradation. More recently, studies have highlighted its crucial role in gene regulation and other important cellular processes. Defects in the nuclear envelope and associated proteins have been linked with several human diseases, including premature ageing syndromes (Worman et al, 2010). Barrier-to-Autointegration Factor (Banf1/BAF) is a small non-specific DNA binding protein, conserved amongst multicellular eukaryotes. Banf was initially identified for its capacity to inhibit autointegration of retroviruses, such as HIV, into their genome (Chen and Engelman, 1998).
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