Final Report Summary - CHROMOREPAIR (Genome Maintenance in the Context of Chromatin)
DNA damage is a well-established source of cancer and ageing. However, the nature of the endogenous source of DNA damage that is most relevant is still a matter of intense debate. Within this context, our laboratory has always focused its research in trying to understand how chromatin and DNA structures can influence the stability of the genome. CHROMOREPAIR has now allowed us to widen the scope of our studies, and to extend our findings into novel areas that intimately relate to chromatin, DNA damage, cancer and ageing.
Previous to this ERC Starting Grant, my work mostly focused on the role of histone modifications on DNA Repair, specifically on the phosphorylation of histone H2A variant H2AX. This was a legacy from my postdoctoral research at the National Cancer Institute, where I was heavily involved in H2AX research, and was a safe way to start my independent laboratory. With the help of the ERC Starting Grant, we have now investigated the roles of additional histone modifications such as ubiquitynilation (RNF8-dependent) and acetylation (Sirtuin-dependent) in DNA repair. We also contributed to studies on the role of the C-terminal tail of histone H2A in chromatin dynamics. In addition to these published stories, we have also explored the role of histone methylations in DNA repair and the maintenance of genomic integrity. In this area, we have developed murine models of a protein known as L3MBTL1, and which is thought to remodel chromatin through its binding to methylated histones. To what extent histone methylations and chromatin compaction shape genome integrity is still not fully understood, and we believe that these models might help us get some insights in this regard. Besides chromatin modifications, part of our work has also been dedicated to understand the role of protein domains that bind histone modifications, and how these domains help DNA Repair proteins in the recognition of DNA breaks. Specifically, we now have a model that explains the role of chromatin-binding domains on a protein named 53BP1, a key player of the response to DNA breaks. Some of these ideas are now being evolved into manuscripts that will appear beyond the timeline of the project. Finally, the ERC Starting Grant allowed us to expand our investigations to additional chromatin-related complexes that might be important in safeguarding genomic integrity. We have extensively investigated the role of the SMC5/6 complex in mammals, a complex related to condensin and cohesin complexes that regulate chromosome structure. This complex forms a ring that embraces DNA, but how this activity is important to protect the genome is largely unknown. We have now finalized a 6-year study that shows that SMC5/6 protects from cancer and ageing in mammals, and are confident that this study will be an important contribution to the scientific community and published prominently.
Importantly, and besides the study of chromatin-related proteins, we have also investigated on how abnormal DNA structures (such as the accumulation of large exposed patches of single-stranded DNA) have an impact on the integrity of mammalian genomes. We discovered that an excessive accumulation of ssDNA (also known as replicative stress; RS) is sufficient to accelerate mammalian ageing. For this, we developed a mouse model of a human hereditary disease known as the Seckel Syndrome, which was the first mouse to ever recapitulate a human disease based on a mutation that impacts RNA splicing rates. Interestingly, this work revealed that an intrauterine accumulation of RS can accelerate ageing later in life. In other words, our studies revealed that ageing rates can be affected by intrauterine distress. Ageing aside, most of our recent research has focused in trying to investigate how RS impacts on cancer development. In a nutshell, we have shown that the high levels of RS that exist in cancer cells can be exploited for the treatment of tumors. First through mouse genetics, but now with the use of drugs that were developed in our laboratory, we have provided evidence that targeting RS-protective pathways (i.e. the ATR kinase) is particularly toxic for cancer cells. These drugs have now reached an advanced preclinical stage and licensed to the Pharmaceutical Industry so that they can be developed into actual clinically valid drugs for their use in cancer treatment.
In summary, CHROMOREPAIR has widely covered the study of how both components of CHROMATIN (proteins and DNA) influence genomic integrity in mammalian cells. The results of these studies have implications for our knowledge on how cancer and ageing arise in mammals, as well as potential to evolve into actual treatments that can have a direct impact on a subset of cancer patients.
Previous to this ERC Starting Grant, my work mostly focused on the role of histone modifications on DNA Repair, specifically on the phosphorylation of histone H2A variant H2AX. This was a legacy from my postdoctoral research at the National Cancer Institute, where I was heavily involved in H2AX research, and was a safe way to start my independent laboratory. With the help of the ERC Starting Grant, we have now investigated the roles of additional histone modifications such as ubiquitynilation (RNF8-dependent) and acetylation (Sirtuin-dependent) in DNA repair. We also contributed to studies on the role of the C-terminal tail of histone H2A in chromatin dynamics. In addition to these published stories, we have also explored the role of histone methylations in DNA repair and the maintenance of genomic integrity. In this area, we have developed murine models of a protein known as L3MBTL1, and which is thought to remodel chromatin through its binding to methylated histones. To what extent histone methylations and chromatin compaction shape genome integrity is still not fully understood, and we believe that these models might help us get some insights in this regard. Besides chromatin modifications, part of our work has also been dedicated to understand the role of protein domains that bind histone modifications, and how these domains help DNA Repair proteins in the recognition of DNA breaks. Specifically, we now have a model that explains the role of chromatin-binding domains on a protein named 53BP1, a key player of the response to DNA breaks. Some of these ideas are now being evolved into manuscripts that will appear beyond the timeline of the project. Finally, the ERC Starting Grant allowed us to expand our investigations to additional chromatin-related complexes that might be important in safeguarding genomic integrity. We have extensively investigated the role of the SMC5/6 complex in mammals, a complex related to condensin and cohesin complexes that regulate chromosome structure. This complex forms a ring that embraces DNA, but how this activity is important to protect the genome is largely unknown. We have now finalized a 6-year study that shows that SMC5/6 protects from cancer and ageing in mammals, and are confident that this study will be an important contribution to the scientific community and published prominently.
Importantly, and besides the study of chromatin-related proteins, we have also investigated on how abnormal DNA structures (such as the accumulation of large exposed patches of single-stranded DNA) have an impact on the integrity of mammalian genomes. We discovered that an excessive accumulation of ssDNA (also known as replicative stress; RS) is sufficient to accelerate mammalian ageing. For this, we developed a mouse model of a human hereditary disease known as the Seckel Syndrome, which was the first mouse to ever recapitulate a human disease based on a mutation that impacts RNA splicing rates. Interestingly, this work revealed that an intrauterine accumulation of RS can accelerate ageing later in life. In other words, our studies revealed that ageing rates can be affected by intrauterine distress. Ageing aside, most of our recent research has focused in trying to investigate how RS impacts on cancer development. In a nutshell, we have shown that the high levels of RS that exist in cancer cells can be exploited for the treatment of tumors. First through mouse genetics, but now with the use of drugs that were developed in our laboratory, we have provided evidence that targeting RS-protective pathways (i.e. the ATR kinase) is particularly toxic for cancer cells. These drugs have now reached an advanced preclinical stage and licensed to the Pharmaceutical Industry so that they can be developed into actual clinically valid drugs for their use in cancer treatment.
In summary, CHROMOREPAIR has widely covered the study of how both components of CHROMATIN (proteins and DNA) influence genomic integrity in mammalian cells. The results of these studies have implications for our knowledge on how cancer and ageing arise in mammals, as well as potential to evolve into actual treatments that can have a direct impact on a subset of cancer patients.