Cell studies link TONSL recognition of histone H3.1 to DNA repair

A University of Ottawa-led study reports that the TONSL protein recognizes several chemical modifications on the histone variant H3.1, helping coordinate DNA repair as cells prepare to divide. The peer-reviewed research, published in Science Advances, also found that mutations in a disease-associated region of TONSL weakened H3.1 recognition and failed to restore normal DNA repair function in human cells. The results offer a molecular explanation for how mutations in TONSL may contribute to sponastrime dysplasia, an ultra-rare inherited skeletal disorder, while remaining a cell-based finding rather than evidence of a clinical treatment.

DNA repair requires proteins both to carry out repairs and to recognize molecular signals associated with when and where repair is needed. Dr. Jean-François Couture, a full professor in the University of Ottawa Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and the study’s co-corresponding author, said the work shows how changes that interfere with this recognition can compromise repair, threaten genome stability and ultimately contribute to disease. TONSL, a protein involved in maintaining genome integrity, emerged from the study as a central coordinator in this process.

The researchers found that TONSL interacts with H3.1 through several molecular binding pockets rather than through a single point of contact. Two pockets recognized specific modifications on the histone: methylation at one position and acetylation at another. These chemical marks are associated with DNA regions involved in regulating genes. Their results therefore indicate that DNA-repair recognition depends partly on the modification state of surrounding chromatin, including histone variants that can carry distinct molecular features recognized by other proteins. The binding pockets collectively allowed TONSL to interpret multiple signals associated with H3.1.

Human-cell experiments provided a disease-related test of this recognition mechanism. Mutations in a region of TONSL associated with sponastrime dysplasia weakened the protein’s ability to recognize H3.1, and the altered proteins failed to restore normal DNA repair function. Couture described this as evidence that the mutations disrupt the ability to coordinate repair machinery as cells prepare for division, allowing DNA damage to accumulate. The findings support a possible contribution of defective TONSL recognition to sponastrime dysplasia; they do not establish that the entire spectrum of the inherited skeletal disorder can be explained by this molecular defect.

The study builds on the team’s earlier work published in Science in 2022. Since then, new collaborations enabled the researchers to extend their analysis from isolated proteins to interactions involving living human and mammalian cells, providing a broader view of how TONSL and H3.1 behave in cellular systems. Dr. Hossein Davarinejad, the first author and a postdoctoral fellow in Couture’s laboratory, said the team next plans to investigate other proteins involved in DNA repair pathways and conduct structural studies of larger parts of the repair machinery. Overall, the experiments show that protecting genetic information involves more than executing repair: the repair system must also interpret the chemical features of chromatin to coordinate the response appropriately.

Subject of Research: Molecular recognition of histone H3.1 modifications by TONSL in DNA repair and genome stability

Article Title: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint

Article References: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: TONSL, DNA repair, histone H3.1, genome stability, chromatin, protein recognition, sponastrime dysplasia, cell division, University of Ottawa, Unravelling, repair, uOttawa-led