ATAD2 controls chromatin-bound HIRA turnover

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.

Structure of the Human ATAD2 AAA+ Histone Chaperone Reveals Mechanism of Regulation and Inter-subunit Communication

“…Building on such discoveries from yeast, studies in mammalian cells are beginning to uncover the molecular relationship between human ATAD2 and chromatin. Consistent with roles as a histone chaperone, ATAD2 functions as a generalist facilitator of chromatin dynamics in human ES cells 24 , and also opposes the activity of the HIRA and FACT histone chaperones by limiting their residence times on chromatin 25 . The potential importance of ATAD2 in chromatin replication has also been explored by a study showing the recruitment of ATAD2 to replication sites during S phase 26 .…”

Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models

“…NH 4 Cl solution (400 mL) and brine (500 mL), dried over MgSO 4 , filtered, and evaporated to afford (S)-(9H-fluoren-9-yl)methyl (1-((2,2dimethoxyethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate 29 (104 g, 100%) as a cream colored solid which was used directly in the next stage. (1R,5S)-11-(4-Hydroxy-3,5-dimethoxybenzoyl)-2,3,5,6-tetrahydro-1,5-epiminobenzo[d]azocin-4(1H)-one (8). DIPEA (0.186 mL, 1.06 mmol) was added to (1R,5S)-2,3,5,6-tetrahydro-1,5epiminobenzo[d]azocin-4(1H)-one 31 (100 mg, 0.53 mmol), 4hydroxy-3,5-dimethoxybenzoic acid (105 mg, 0.53 mmol) and HATU (303 mg, 0.80 mmol) in DCM (5 mL).…”

“…Furthermore, modulation of ATAD2 expression using siRNA attenuates proliferation and invasiveness, promotes apoptosis, 7 and regulates chromatic dynamics. 1,8 These findings led to us to the hypothesis that cell lines with increased ATAD2 copy numbers and high expression (for example, EVSA-T or SK-BR-3) would show increased sensitivity to ATAD2 inhibitors. If so, we surmised it may be possible to use ATAD2 expression levels as a patient selection strategy in triple negative breast cancer, thereby creating a clear line of sight to targeted clinical benefit, with identification of the "right patient" being a key "5R" requirement of drug projects in AstraZeneca.…”

“…It is overexpressed in many cancers due to coamplification with c-Myc and is a marker of poor prognosis in colorectal, breast and lung, endometrial, and ovarian cancers. Furthermore, modulation of ATAD2 expression using siRNA attenuates proliferation and invasiveness, promotes apoptosis, and regulates chromatic dynamics. , …”

Tumor-Promoting ATAD2 and Its Preclinical Challenges

“…ATAD2 also controls the dynamics of histone chaperone and chromatin interactions, particularly the histone chaperone HIRA. ATAD2 deletion would significantly reduce histone chaperone and chromatin interactions, causing an accumulation of histone chaperones at the active gene transcription start site, which leads to a disruption of the nucleosome assembly–disassembly balance, resulting in a net increase in nucleosome assembly [ 101 ].…”