CHROMATIN REMODELING AT THE INTERFACE OF CELLULAR PROCESSES AND GENETIC MODIFICATIONS
“When I started my independent research we were working on histone modifications, an important epigenetic mechanism encompassing post-translational markings of histones. The generous support of la Fondation ARC came at the right time because we were interested in mechanisms and wanted to exploit the cellular and mouse models that we had generated”, explains Zdenko Herceg.
Histones are essential specialized proteins responsible for the packaging of DNA into chromatin. Changes in chromatin compaction states (open versus condensed) occur through different modifications on histones, such as acetylation, methylation, phosphorylation and ubiquitination. Each of them, by modifying the histone N-terminal tails, alters the chromatin structure and may affect gene transcription.
Histone acetylation is carried out by Histone Acetyl Transferases (HATs). These enzymes acetylate the lysine residue of histone tails, allowing chromatin relaxation and transcription activation. Many cofactors act in coordination with complexes displaying HAT activity, such as TRRAP (Transactivation Transformation Domain-Associated Protein) . To study the functional significance of histone modifications in cellular processes and cancer, Zdenko Herceg and his group generated modified mouse and cellular models that allow inactivation of histone acetylation using a genetic approach, in vitro and in vivo. For this, TRRAP was inactivated in conditional knock-out mice (and cell lines derived from these mice) as well as in different human cancer cell lines.
They showed that histone acetylation, mediated by the HAT/TRRAP complex, is involved in cell cycle control, by regulating genes involved in chromosome segregation during cell division (mitosis) . They also explored the relationship between chromatin compaction and specific DNA repair pathways that counteract potentially disastrous cellular effects of DNA breaks. Indeed, many endogenous or exogenous factors continuously damage the DNA. These DNA lesions, if left unrepaired, may induce cell death (apoptosis) or cell senescence. Some DNA lesions also cause mutations in the nucleotide sequence and others, such as DNA double strand breaks, induce chromosomal aberrations, both driving tumorigenesis.
The different lesions are handled by dedicated repair pathways. Dr Herceg has concentrated in the repair of double-strand breaks (DSBs) and the role of histone modifications in this process. These cytotoxic lesions are caused by ionizing radiation and replication stress, as well as physiological processes. DSBs are handled by two DSB repair pathways, one of which is Homologous Recombination (HR), which is based on the exchange of genetic information between homologous molecules and is critical for genomic stability. The detection, signaling and initiation of DSBs repair involve the MRN (MRE11-RAD50-NBS1) complex, after which a whole cascade of events is triggered, and many proteins are recruited to handle the damage. Zdenko has shown that histone acetylation, mediated by TRRAP associated to the HAT Tip 60, is essential for DSB repair by HR . Moreover TRRAP, through its interaction with the MRN complex, is directly involved in DSB repair .
DNA repair pathways are only a part of the impressive multi-faceted network of genome surveillance mechanisms that has evolved in response to DNA lesions, including a modulation of the cell cycle via the activation of several cell cycle checkpoints. To a great extent, this work sheds new light on how histone acetylation might regulate and coordinate these intricate processes.
As the scientist explains, “histone modifications are traditionally associated with gene expression and we discovered that histone acetylation is also important for DNA repair, transcription and other chromatin-based processes. That was unexpected and it is an important discovery which tells us how deregulated epigenetic mechanisms and aberrant changes in the epigenome could promote genetic changes”. Interestingly, recent sequencing studies revealed that the genes coding for histone modification enzymes are recurrently mutated in many cancers, consistent with the notion that disruption of epigenetic mechanisms promotes cancer development and progression. As such, they represent potential therapeutic targets. Together, these discoveries underlie new mechanisms connecting histone modifications and tumorigenesis.
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