The Role of Chromatin in DNA Repair

In cells, DNA wraps around proteins called histones to form a nucleoprotein complex known as chromatin. Due to its organization and structure, chromatin contributes to the DNA damage response (DDR), whose purpose is to preserve the integrity of the genome against mutations and other chromosomal aberrations, by facilitating the repair of DNA damage caused by endogenous or exogenous sources such as radiation, chemicals, and metabolic byproducts. This role is essential for maintaining cellular function and preventing diseases characterized by genomic instability, such as cancer.The team is studying the role of chromatin in the DNA damage response within human cells to better understand a biological process in which many mechanisms remain to be characterized.

Objectives

To understand how chromatin-related factors contribute to the DNA damage response and maintain genomic integrity in human cells, and how alterations in these factors—such as mutations or expression dysregulations—disrupt this response and induce genomic instability in the context of diseases, particularly cancer.

We seek to answer broad questions: How do chromatin-related factors contribute to the DNA damage response, and how does their pathological dysfunction compromise genomic integrity in cancer cells?

Despite the significant knowledge gained over the past few decades, we still lack a comprehensive understanding of how chromatin induces proteomic, metabolic, and post-translational changesat the level of DNA damage detected during DNA synthesis, nor do we fully understand how these factors regulate damage detection, the activation of repair pathways, and the faithful replication of the (epi)genome. We must also analyze how aberrant chromatin organization in cancer cells compromises genome integrity while sustaining proliferation—vulnerabilities that could be targeted to promote the destruction of cancer cells.

Approaches

We focus on DNA damage induced by replication stress—any source, whether endogenous or exogenous, that interferes with the progression of the replication fork and the faithful duplication of the epigenome. We study chromatin function by analyzing how proteomic, metabolic, and post-translational modifications that occur during DNA damage influence the activation of repair pathways, genome duplication, and epigenome restoration following synthesis (Figure 1). To achieve this goal, we are implementing and utilizing genomic editing of human cell lines, CRISPR screens, high-throughput imaging, in silico predictions of protein-protein interactions, and proteomic approaches tailored to chromatin factors (Figure 2).