Molecular Biology Research

Cancer: Faulty DNA or Faulty DNA Repair Systems

9.11.2016 | Cancer can occur when things go wrong in our genes, but also when the processes to fix damaged genes goes wrong. AcademiaNet members Dr. Elisabetta Citterio, Dr. Michela Di Virgilio, Dr. Jacqueline Jacobs and Prof. Rocio Sotillo study the mechanisms of DNA repair and their link to cancer.
The DNA in our cells can be damaged in dangerous ways by factors like tobacco smoke and sunlight, as well as by normal cellular processes. Molecular pathways in cells respond by repairing the broken DNA or making sure that the cell stops dividing or dies when the damage is too extensive to be repaired. If damaged DNA is not repaired quickly and accurately, the genome can become unstable and the cell might become cancerous. Several women who are members of AcademiaNet research DNA repair mechanisms and their role in preventing or promoting cancer.

Dr. Elisabetta Citterio
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Dr. Elisabetta Citterio
Dr. Elisabetta Citterio, Associate Staff Scientist at the Netherlands Cancer Institute in Amsterdam, studies double-strand breaks in DNA and how a type of reversible modification of the units that package genetic material within cells targets the repair response to the faulty DNA. Double-strand breaks are when both of the chains in the DNA double helix structure are broken. This type of DNA damage can be caused by radiation, chemical agents or ultraviolet light and is one of the most dangerous types of DNA breaks.

DNA is wrapped around proteins called histones, which help to squeeze the long strands of DNA into the cell nucleus. When a double-strand DNA break occurs, the histones at each end of the DNA break are modified. This involves 'labeling' the break by coupling a protein called ubiquitin (a process known as ubiquitination) to the histones, which directs the various molecules required for DNA repair to the broken portion of DNA. Dr. Citterio's work has shown that the timely removal of ubiquitin ('deubiquitination') by a specific protein called 'human ubiquitin-specific protease 3' is very important for efficient repair of the DNA breaks. By promoting DNA repair, ubiquitin-specific protease 3 helps to prevent the accumulation of multiple DNA breaks in human cells and to reduce the risk of cancer.

Dr. Michela Di Virgilio
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Dr. Michela Di Virgilio
Dr. Michela Di Virgilio, Head of the DNA Repair and Maintenance of Genome Stability Group at the Max Delbrück Center for Molecular Medicine in Berlin, also studies the mechanisms by which double-strand DNA breaks are repaired. Her work looks at how these types of break are channelled into specific repair processes.
Two main processes are available to mend double-strand DNA breaks: The first is directly joining the ends back together without any processing (non-homologous end-joining). The second is repairing the break by copying the information from an intact matching DNA molecule, in an approach that relies on extensive processing of the DNA ends (homologous recombination). These two mechanisms cannot be used interchangeably to repair double-strand DNA breaks, because breaks need to be repaired by a specific process according to the cellular context.

Dr. Di Virgilio and her team investigate how the repair pathway is chosen for double-strand DNA breaks. The key regulator of this process is a protein called 53BP1. 53BP1 is a DNA repair factor that marks the loose ends of broken DNA. Protection of the DNA ends by 53BP1 ensures that the DNA is repaired by non-homologous end-joining. In situations where cells have to use the homologous recombination type of repair, the DNA repair protein BRCA1 displaces 53BP1 to allow this alternative repair process to take place.

This process goes awry in cells that do not have a working copy of the BRCA1 gene, which is frequently mutated in hereditary breast and ovarian cancers. As a result, DNA double-strand breaks that should be mended by homologous recombination are instead fixed with non-homologous end-joining, causing genomic instability and predisposing the cell to carcinogenesis. Dr. Di Virgilio's research has shown that 53BP1 needs to be phosphorylated first before it can recruit factors that protect the DNA ends such as the DNA damage response proteins Rif1 and PTIP, which in turn are key factors in promoting genome instability in BRCA1-deficient cells.

Dr. Jacqeline Jacobs
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Dr. Jacqeline Jacobs
Dr. Jacqueline Jacobs, Group Leader in the Division of Molecular Oncology at the Netherlands Cancer Institute, looks in a different way at how DNA ends are detected and processed by DNA repair pathways. DNA strands are packed into chromosomes, the ends of which are capped with structures called telomeres that prevent the ends from being identified as DNA breaks. Telomeres can become 'worn away' during multiple rounds of cell division, activating a DNA damage response that forces the cell to stop dividing (senescence) or die (apoptosis). Cell division that exhausts telomeric DNA, difficulties in replication of telomeres and errors in telomere capping proteins can cause cells to lose proper telomere protection and instead accidentally undergo DNA repair at chromosome ends. This wrongful repair causes chromosomes to fuse end to end, leading to genome instability and ultimately cancer if such cells are not eliminated.

Dr. Jacobs and her team combine functional genetics with a method for inducible and reversible telomere deprotection to search for factors that act in DNA damage responses at telomeres. They have found that a protein called MAD2L2 localises deprotected telomeres and promotes fusion of chromosome ends by non-homologous end-joining, causing genomic instability. MAD2L2 also accumulates at DNA double-strand breaks caused by radiation and promotes end-joining of these breaks.

Prof. Rocio Sotillo
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Prof. Rocio Sotillo
Chromosome instability is the research topic of Prof. Rocio Sotillo, head of the Molecular Thoracic Oncology Group at the German Cancer Research Canter in Heidelberg. Prof. Sotillo specifically studies the part of cell division where newly copied chromosomes are separated into the two new cells. A group of 'checkpoint' proteins, such as MAD2 and HEC1, increase during this part of cell division and act to make sure the new cells have the correct number of chromosomes. Prof. Sotillo's research has shown that mice that overexpress the gene for MAD2 or HEC1 have abnormal numbers of chromosomes in their cells (aneuploidy) and develop aggressive tumours in multiple organs.

Another of Prof. Sotillo's studies looked at when the gene Mad2 was overexpressed at the same time as the cancer-causing gene Kras in the lung or in the breast of animals. These animals could initially be cured of cancer by therapies that prevented the activity of Kras, but would then relapse even though Kras had been inhibited. This finding suggests that the aneuploidy induced by Mad2 during tumour progression allows the cancer to evade therapies that target Kras. Prof Sotillo's hypothesis is that chromosome instability might produce more genetic diversity within cancer cells or enhance the rate of mutations, which could allow cancer cells to acquire harmful genetic changes that cannot be stopped by the usual DNA repair pathways.

By understanding how our cells repair the dangerous faults in our genes, both correctly and incorrectly, these researchers hope to identify pathways and molecules that can be targeted by drugs. The end goal is to develop novel treatments that ensure that cells with faulty DNA are fixed properly or stop dividing, so there is no risk they may cause cancer. For cancer that has already developed, these researchers hope to identify ways to improve the effectiveness of treatments that act by damaging the cancer cells' DNA.
  (© AcademiaNet)
Helen Jaques

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