In an article published in the May 22, 2023 issue of Cell Systems, a team of diverse scientists, led by researchers from the University of California San Diego School of Medicine, has developed an innovative map that unveils the intricate system within the human body responsible for addressing and repairing DNA damage—a crucial factor in the onset and progression of various diseases.

DNA damage and replication errors resulting from stress and other factors play a significant role in the development of diseases such as cancer and heritable neurological disorders. To maintain genomic integrity and support overall health, cells have evolved a sophisticated network of cell-cycle checkpoints and DNA damage repair tools collectively known as the DNA damage response (DDR).

Defects in DDR have been associated with numerous diseases, underscoring the importance of understanding its mechanisms to identify potential therapeutic strategies. Senior author Trey Ideker, Ph.D., professor at UC San Diego School of Medicine and UC San Diego Moores Cancer Center, highlights the complexity of DDR, involving hundreds of proteins assembling in different ways to address various challenges. He emphasizes that comprehending how DDR functions is vital before attempting to intervene.

The recent paper by Ideker and colleagues represents a significant advancement in elucidating the complexities and functions of DDR through the creation of a multi-scale map of protein assemblies. Unlike earlier maps that relied on published scientific literature, which often presented conflicting findings and focused predominantly on well-studied mechanisms, this new reference map utilizes affinity purification mass spectrometry and a broad collection of multi-omics data. The resulting map provides a more comprehensive picture, featuring a hierarchical organization of 605 proteins grouped into 109 assemblies. It captures canonical repair mechanisms while proposing new DDR-associated proteins linked to stress, transport, and chromatin functions within cells.

This study introduces the concept of multi-omics, an approach that combines data sets from different omics disciplines to gain a holistic and nuanced understanding of whole systems and organisms. Within the cell, various molecular processes such as genomics, transcriptomics, and proteomics involve interactions between thousands of genes, transcripts, or proteins. While scientists have traditionally taken a reductionist view, examining omics processes individually, the emerging field of systems biology considers these processes simultaneously, using tools like machine learning to evaluate the extent to which different molecular processes influence interactions within whole systems and networks.

First author Anton Kratz, Ph.D., formerly a research scientist in Ideker’s lab and now working at The System Biology Institute in Tokyo, Japan, highlights the potential of large-scale experimental screens to capture interactions between genes or proteins that go beyond what is described in the literature. These screens can serve as a basis for data-driven maps of DDR, providing valuable insights.

However, screening presents challenges as different methods may measure molecular processes in isolation, potentially missing interactions that occur only under specific stresses or conditions. To address this, the researchers measured new protein-protein interaction networks centered around 21 key DDR factors with and without DNA damage. They developed a machine learning approach to integrate new and existing data, along with statistical analysis that significantly informed the resulting map.

Kratz emphasizes two revelatory aspects of the study. Firstly, the abundance of novel proteins in the map, with approximately 50% of the proteins following a data-driven approach not found in the literature-curated maps, justifying the need for a data-driven construction. Secondly, the membership to DDR exists on a continuum, extending to stress, transport, and chromatin functions, highlighting the complex nature of DDR.

The comprehensive map of DDR generated by this study serves as a valuable resource for further research into DNA repair mechanisms and offers new insights that could potentially lead to the development of targeted therapies for various diseases.

By Impact Lab