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Abstract
Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and Schizosaccharomyces pombe to investigate ATAD2's conserved functions. In S. pombe, the deletion of ATAD2 ortholog, abo1, leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the histone chaperone HIRA. In human cancer cell lines and in mouse embryonic stem cells, we observed that the KO of ATAD2 leads to an accumulation of HIRA. A ChIP-seq mapping of nucleosome-bound HIRA and FACT in Atad2 KO mouse ES cells demonstrated that both chaperones are trapped on nucleosomes at the transcription start sites of active genes, resulting in the abnormal presence of a chaperone-bound nucleosome on the TSS-associated nucleosome-free regions. Overall, these data highlight an important layer of regulation of chromatin dynamics ensuring the turnover of histone-bound chaperones.
Highlights
ATAD2 belongs to the large AAA-ATPase family involved in a variety of cellular functions (Boussouar et al, 2013; Cattaneo et al, 2014; Nayak et al, 2019)
The Atad2-dependent histone turnover discovered in mouse embryonic stem (ES) cells (Morozumi et al, 2016) prompted us to exploit the evolutionary conservation of Atad2 (Fig 1A) in the fission yeast S. pombe, to learn more about possible molecular mechanisms that could link Atad2’s function to histone turnover
Two other single-nucleotide variants (SNVs) mapped to the slm9 gene, which encodes another subunit of the HIRA complex
Summary
ATAD2 belongs to the large AAA-ATPase family involved in a variety of cellular functions (Boussouar et al, 2013; Cattaneo et al, 2014; Nayak et al, 2019). ATAD2 bears a bromodomain whose preferential cognate ligand is a histone H4 tail peptide acetylated at lysine 5 and lysine 12 (Caron et al, 2010; Koo et al, 2016; Morozumi et al, 2016), a signature of neo-synthesized H4. This particular domain clearly ranks ATAD2 among the chromatin binders and suggests a role as a regulator of chromatin structure and functions, and possibly histone deposition. Its activation in all cancers prompted investigators to classify the gene among the most frequently activated members of the so-called cancer/testis (C/T) gene family (Caron et al, 2010)
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