ATAD2: New Insights Into Its Role in Ovarian Disease

ATAD2 has emerged as a protein of interest in various diseases, including ovarian pathology. As a chromatin-associated factor, it influences gene regulation and cellular processes that may contribute to disease progression. Understanding its function could provide new avenues for diagnostics and treatment strategies.

Recent studies suggest ATAD2 plays a role in tumor biology and broader physiological functions, making further investigation crucial.

Molecular Composition And Structure

ATAD2, or ATPase family AAA domain-containing protein 2, is a chromatin-associated factor characterized by its ATPase activity and bromodomain, which facilitate chromatin remodeling and transcriptional regulation. It belongs to the AAA+ (ATPases Associated with diverse cellular Activities) superfamily, a group of ATP-dependent molecular machines involved in various cellular processes. Structurally, ATAD2 contains a conserved ATPase domain that hydrolyzes ATP to provide energy for chromatin dynamics. This function is essential for nucleosome repositioning, allowing transcriptional machinery access to DNA.

The bromodomain enables ATAD2 to recognize and bind acetylated lysine residues on histone tails, a key mechanism in epigenetic regulation. Histone acetylation is a hallmark of transcriptionally active chromatin, and by engaging with acetylated histones, ATAD2 recruits additional regulatory proteins to influence gene expression. Structural studies using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy have revealed its preference for histone H3 and H4 acetylation marks, commonly associated with active transcriptional sites.

Beyond its ATPase and bromodomain functions, ATAD2 possesses intrinsically disordered regions (IDRs) that contribute to dynamic interactions with chromatin and nuclear proteins. These IDRs provide structural flexibility, enabling ATAD2 to participate in phase-separated nuclear compartments, such as transcriptional condensates. This property is particularly relevant in rapidly proliferating cells, where chromatin accessibility must be tightly regulated. Cryo-electron microscopy studies suggest ATAD2 functions as part of larger chromatin remodeling complexes, interacting with histone chaperones and transcription factors.

Biological Roles In The Cell

ATAD2 integrates ATPase-driven remodeling with epigenetic signaling to influence transcriptional activity. By binding acetylated histones, it regulates chromatin accessibility and gene expression, particularly in proliferative environments. Chromatin immunoprecipitation sequencing (ChIP-seq) studies show ATAD2 localizes to transcriptionally active regions, especially enhancers and promoters enriched with histone H3 acetylation marks. This positioning suggests a role in maintaining an open chromatin state, facilitating efficient transcription.

ATAD2 is also involved in chromatin dynamics during DNA replication. Its ATPase activity contributes to nucleosome disassembly and reassembly, ensuring replication fork progression. siRNA-mediated knockdown studies indicate that ATAD2 depletion leads to replication stress, characterized by increased fork stalling and DNA damage accumulation. This finding aligns with its upregulation in rapidly dividing cells, where genomic stability is crucial.

Additionally, ATAD2 responds to metabolic and oxidative stress, linking its ATP-dependent remodeling activity to cellular energy fluctuations. Proteomic analyses have identified interactions between ATAD2 and chromatin remodelers involved in stress-induced transcriptional reprogramming, underscoring its role in adaptive gene expression changes.

Expression Patterns In Tissues

ATAD2 expression varies significantly across tissues, with the highest levels in highly proliferative environments such as the testes, bone marrow, and epithelial linings. Single-cell RNA sequencing data show peak expression in spermatogenic cells, highlighting its role in chromatin reorganization during gametogenesis.

While most prominent in dividing cells, ATAD2 is also detectable in certain differentiated tissues, including the liver and lungs, where its expression appears inducible in response to metabolic stress. In hepatocytes, for example, ATAD2 levels rise under metabolic challenges, suggesting a role in adaptive gene regulation.

In contrast, ATAD2 is largely absent from quiescent tissues such as skeletal muscle and neurons, reinforcing its link to cellular proliferation. However, under pathological conditions like fibrosis, ATAD2 can be re-expressed in otherwise quiescent cells, possibly as part of a transient regenerative response. This reactivation has been noted in fibrotic lung tissue, where ATAD2-positive fibroblasts appear in remodeling areas.

Relevance In Ovarian Pathology

ATAD2 overexpression has been documented in high-grade serous ovarian carcinoma (HGSOC), the most aggressive ovarian cancer subtype, where it correlates with poor prognosis and increased tumor proliferation. Transcriptomic analyses reveal ATAD2 is frequently upregulated in malignant ovarian tissues compared to normal epithelium, suggesting a role in oncogenic transcriptional programs. Its heightened expression enhances proliferative gene networks regulated by MYC and E2F transcription factors, both implicated in ovarian tumorigenesis.

Beyond promoting proliferation, ATAD2 contributes to chemotherapy resistance. Studies on platinum-based treatments indicate that ATAD2 overexpression coincides with reduced cisplatin sensitivity. This resistance may stem from ATAD2’s role in maintaining an open chromatin state, facilitating efficient DNA repair after chemotherapeutic-induced damage. By enhancing the recruitment of repair proteins to DNA lesions, ATAD2 enables cancer cells to survive genotoxic stress, complicating treatment outcomes.

Associations With Other Conditions

ATAD2 dysregulation is implicated in multiple malignancies, including breast, lung, and hepatocellular carcinomas, where it correlates with tumor aggressiveness and poor prognosis. In breast cancer, ATAD2 enhances estrogen receptor (ER)-mediated transcription, promoting genes involved in cell cycle progression and metastasis. CRISPR-Cas9 knockout models demonstrate that ATAD2 depletion in ER-positive breast cancer cells reduces tumor growth, highlighting its potential as a therapeutic target.

Beyond oncology, ATAD2 has been linked to metabolic disorders. Its expression responds to lipid metabolism cues, with increased levels detected in fatty liver disease and obesity-related hepatic dysfunction. In murine models of diet-induced obesity, ATAD2 upregulation in hepatocytes influences genes involved in lipid synthesis and storage, suggesting a broader role in metabolic regulation. Additionally, rare genetic variants affecting ATAD2 function have been identified in individuals with intellectual disability and autism spectrum disorders, pointing to a potential role in neural chromatin regulation.

Key Laboratory Methods For Investigation

Investigating ATAD2’s functions and pathological relevance requires genomic, proteomic, and functional assays. ChIP-seq has been instrumental in mapping its genomic binding sites, revealing its association with active enhancers and promoters. Coupling ChIP-seq with RNA sequencing helps delineate ATAD2-regulated gene networks, particularly those involved in proliferation and stress responses.

Biochemical and structural studies provide insights into ATAD2’s chromatin interactions. X-ray crystallography and NMR spectroscopy characterize its bromodomain’s binding affinities for acetylated histones. Proteomic techniques such as co-immunoprecipitation and mass spectrometry have identified ATAD2’s interacting partners, including histone chaperones and transcriptional coactivators. Functional assays, including RNA interference and CRISPR-based gene editing, further clarify its role in cellular proliferation, showing that ATAD2 depletion impairs growth and increases DNA damage sensitivity in cancer models.