Newly Discovered Gene ZNF280A: Implications for DNA Repair and Cancer Therapy

Researchers at Boston University Chobanian & Avedisian School of Medicine, Massachusetts General Hospital, and Harvard Medical School have identified a previously uncharacterized gene, ZNF280A, which plays a significant role in the cellular DNA repair process. The findings, published on June 18, 2025, in the journal *Nature Cell Biology*, suggest that ZNF280A could have potential implications for cancer therapy and understanding genomic stability.

Cells are continuously exposed to various internal and external factors that can damage DNA. It is estimated that human cells can accrue up to 100,000 DNA lesions daily, with DNA double-strand breaks (DSBs) being particularly harmful, as they can lead to mutations and even cell death. The ability of cells to manage these lesions relies on a complex series of mechanisms collectively referred to as the DNA damage response (DDR).

Dr. Raul Mostoslavsky, MD, PhD, Scientific Director of the Krantz Family Center for Cancer Research at Massachusetts General Hospital and co-corresponding author of the study, emphasized the importance of ZNF280A in the DNA repair process. "Based on our discovery that ZNF280A is an important new DNA repair protein, we were interested to understand whether patients with the 22q11.2 distal deletion syndrome were experiencing DNA repair defects due to reduced expression of ZNF280A," he stated.

The research team utilized innovative screening methodologies to identify chromatin factors, such as ZNF280A, that are recruited to sites of DNA damage. The study's results indicated that ZNF280A is crucial for repairing DSBs, and its absence is linked to increased DNA damage in cell lines derived from patients with the aforementioned syndrome.

The research also highlighted that ZNF280A resides on chromosome 22 at the 22q11.2 locus, which is frequently deleted in patients with severe clinical features, including cognitive impairments and immune deficiencies. Dr. Thomas L. Clarke, PhD, an assistant professor of pathology and laboratory medicine at Boston University, noted the novelty of the study's approach. "Our study provides strong evidence that our approach exploiting DNA open reading frame (ORF) sequences has the potential to identify uncharacterized chromatin factors essential for DNA repair that may have been missed via conventional screening approaches," he said.

The implications of this research extend beyond understanding DNA repair mechanisms. As ZNF280A is now recognized as a potential target for therapeutic strategies in disorders associated with genomic instability, such as cancer, further investigations into its regulatory mechanisms will be essential. The collaboration with the Children’s Hospital of Philadelphia, a leader in 22q11.2 distal deletion syndrome research, provided validation for the role of ZNF280A, as reintroducing the gene into patient-derived cells partially rescued DNA repair defects.

Dr. Mostoslavsky and his colleagues aim to explore the regulatory pathways of ZNF280A to determine whether it can be targeted therapeutically for conditions related to DNA repair deficiencies. The research represents a significant step forward in understanding the genetic underpinnings of DNA repair and its broader implications for human health and disease management.

The study is titled "ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome" and can be accessed in the June 2025 issue of *Nature Cell Biology* (doi: 10.1038/s41556-025-01674-1).