In‐depth, unbiased studies led to the surprising identification of ZNF280A, an uncharacterized gene previously unknown for its role in DNA repair. This new discovery opens the door to understanding how this important gene regulates cellular responses to DNA damage. It further emphasizes its importance to patients with rare genetic disorders. Our results demonstrate an unambiguous association of ZNF280A with the clinical features observed in patients with 22q11.2 distal deletion syndrome. This syndrome is characterized by a cascade of alarming and conceivably deadly health complications.
Scientists have determined that ZNF280A is drawn to regions of DNA damage. It has a critical function in DNA double-strand break (DSBs) repair. The gene that encodes the ZNF280A protein is found on chromosome 22 at the 22q11.2 locus. The research highlights that loss of this gene is a major force pushing cells to DNA repair failure. Consequently, these deficiencies play a role in the clinical manifestations seen in affected patients.
The Role of ZNF280A in DNA Repair
ZNF280A is a poorly characterized chromatin factor that is specifically required under conditions of DNA damage stress. When ZNF280A is missing, cells find it more difficult to fix double-strand breaks in DNA, recent research found. This inability profoundly limits their ability to protect genomic integrity.
“To date, identification of chromatin factors in DNA repair has been limited due to the lack of high-throughput screening methodologies. Moreover, traditional siRNA screens and more recent CRISPR knockout screening approaches have proved challenging in the context of chromatin factors, due to their essentiality for cell viability.” – Thomas L. Clarke
FTF analysis shows that, when ZNF280A is reintroduced into ZNF280A deficient cells, this can partially restore their ability to repair DNA damage. This finding lays the foundation for exploring downstream therapeutic pathways to overcome potential DNA repair defects caused by loss of ZNF280A.
Clinical Implications of ZNF280A Absence
ZNF280A locus loss in patient tissues results in more severe patient clinical features. This is especially true in individuals with 22q11.2 distal deletion syndrome. These congenital defects include microcephaly—a condition defined by abnormally small head circumference—as well as short stature and other growth abnormalities. In addition to TS-specific defects, patients frequently suffer from non-specific global developmental delays and cognitive impairments.
All of these folks have an indication of immune suppression. As a consequence, many suffer from resultant immune deficiencies that mar their general health and wellbeing. As this pilot study demonstrates, these clinical features are hallmarks of defects in DNA repair mechanisms. These defects and the accompanying genomic instability are associated with the downregulation of ZNF280A.
“Based on our discovery that ZNF280A is an important new DNA repair protein, we were interested to understand whether these patients were experiencing DNA repair defects and genomic instability in their cells, as a direct result of less ZNF280A expression, and wondered if this might explain some of their clinical features.” – Raul Mostoslavsky
A New Understanding of 22q11.2 Deletion Syndrome
The identification of ZNF280A provides an essential new piece to the puzzle of dissecting 22q11.2 distal deletion syndrome. It provides new insights into genetic determinants underlying disease pathogenesis and shows a direct connection between genetic alterations and clinical manifestations observed in affected patients. Such knowledge can inform the development of novel diagnostic and therapeutic strategies to ultimately benefit patients.
As research progresses, the discoveries have repercussions that go much farther than knowing the function of one gene. The current study highlights the potency of chromatin factors in the larger arena of diverse DNA repair pathways. We hope to identify further therapeutic intervention targets by bringing more to light the role of ZNF280A. Their groundbreaking research will help develop new and better treatments for those who are afflicted with these debilitating diseases.