Double Strand Breaks (DSB)

By helping to repair DNA, the BRCA2 protein plays a critical role in maintaining the stability of a cell 's genetic information. The cancer risk caused by BRCA2 mutations is inherited in a dominant fashion, even though usually only one mutated allele is directly inherited. This is because people with the mutation are likely to acquire a second mutation, leading to the dominant expression of the cancer. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations. Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity (LOH). Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell.

Genetic instability refers to temporary or permanent unscheduled alterations within the genome occur and can occur both at chromosomal or nucleotide level. Instability at nucleotide level consists of increased frequency of base-pair mutation or amplified number of nucleotide repeat units such as trinucleotide repeats (TNR) in a gene which will show altered expression and malfunction of RNA and/or protein (Castel et al., 2010).

On December 10, 2015, three profound individuals received the Nobel Prize in chemistry for their work on DNA repair systems. Paul Modrich, Thomas Lindahl, and Aziz Sancar studied how the cell repairs and protects the information held in its DNA; specifically, Paul Modrich focused on DNA mismatch repair. Since DNA constantly replicates, damage and incorrect pairings are expected, but enzymes watch over DNA as it replicates and repair any errors that occur. In the mismatch repair system, enzymes find the mismatch in the copy of DNA, cut the incorrect section out, and replace it with the correct sequence. Paul Modrich’s study of the mismatch repair system has provided the medical field with important information regarding cancer growth and the possibility of a cure.

Dr. Friedman also explained a few of the consequences of improper or unrepaired DSBs can result in cancer, the loss of heterozygosity, or abnormal gene appearance. In regards to this, she depicted two important ways that a cell can go about repairing these breaks. One way is

This process of natural selection can lead to significant changes in the appearance, behavior, or physiology of individuals in a population.Generally, mutation is reversed. DNA repair machines are constantly at work in our cells, fixing mismatched nucleotides and splicing broken DNA strands back together. Yet. some DNA changes remain. If a cell accumulates too many changes—if its DNA is so damaged that repair machinery cannot fix it—it either stops dividing or it self-destructs. If any of these processes go wrong, the cell could become cancerous. Environmental Factors

The first stage consists of a mutation of DNA which does not undergo DNA repair (by enzymes) or undergoes faulty DNA repair.

Along with these three syndromes, there is a disease that can be caused by UPD, which takes about 7.6 million lives every year (Makichima and Maciejewski 2011). Cancer is a disease that is caused by an uncontrolled division of cells in the body. This happens when certain genes that aid in cell division have their signals blocked from their specific receptors. In this way, the cell will mutate by producing several copies of a cell in a small amount of time. In some cases, cancer can be triggered not only by UPD but also by a deletion of certain areas on a certain chromosome (Makichima and Maciejewski 2011). This process is called loss of heterozygosity (LOH). LOH is popular for causing malignant transformations, which will eventually lead to tumor development.

Over the years, evidence has proven that any mutations on chromosomes whether they are broken, missing or repositioned is not just a side effect of cancer, but can be an increasing factor for

In breast cancer, the tumor suppressor genes BRCA1 and BRCA2 germlin mutation is greatly present in women, it’s about 5% to 10% of all breast cancers. These genes normally involved in major cellular functions include double-strand break repair, checkpoint control, transcription regulation, and chromatin remodeling, and its inactivation may lead to spontaneous abnormalities in DNA, this might promote neoplastic development. Mutations of some genes (ATM and CHEK2) also affect BRCA pathways. The improved understanding of BRCA1 and 2 function of normal and cancer cell is related to DNA repair and therapeutic responses. Gene expression profiling is to identify distinct subtypes of breast cancer, which have

Telomerase (TERT) is an enzyme responsible for maintaining the ends of telomeres and reversing the process of telomere shortening in humans by adding a “TTAGGG” polynucleotide to the 3’ end of the telomere. The addition of the “TTAGGG” compensates for inefficiencies in replication of the ends of DNA in eukaryotes. Telomerase is limited to highly proliferative cells such as germ cells and lymphocytes where the telomerase is necessary to maintain telomere length, and the telomeres themselves are not sufficiently long to facilitate such rapid cell division without incurring damage to the DNA. Most somatic cells exhibit no telomerase activity and in cells where telomerase is present telomerase activity is strictly regulated. In cells that exhibit

One explanation as to how x-rays effect cells is that the radiation causes double-strand breaks (DSBs). A double strand break is a lesion within DNA which can prevent replication, cause deletions, or cause translocations of the DNA. All of the named effects have the potential to cause a mutation to a cell (Negritto, 2010). Double-strand breaks are known as genomic rearrangements because it has been shown to change the genetic code of a cell. All of the effects of DSBs may lead to an increase in the recombination of genes in chromosomes, which may explain how the cells are mutated. In one experiment, cells were exposed to x-ray radiation in order to test the frequency of DSB. H2AX is a type of proteins that repairs double-strand breaks

The DNA then tries to repair itself, however this process is extremely error prone and the mutations are random. Again, researchers have found that this step can be manipulated to have their chosen effect by inserting another section of DNA that contains the desired sequence. This template can recombine as part of the strand replacing the original sequence with this new version.

Deinococcus accomplishes its resistance to radiation by having multiple copies of its genome and rapid DNA repair mechanisms. It usually repairs breaks in its chromosomes within 12–24 hours through a 2-step process. First, D. radiodurans reconnects some chromosome fragments through a process called single-stranded annealing. In the second step, a protein mends double-strand breaks through homologous recombination. This process does not introduce any more mutations than a normal round of replication would.

There are two types of editing that are commonly used: homologous recombination and non-homologous end joining(NHEJ). Homologous recombination utilizes a repair template The desired changes, such as gene knock out, gene tagging, and specific mutations, are flanked by left and right homologous arm sequences. Upon double cross over the desired changes integrate into the genome. In non-homologous end joining the ends are joined together and introduce random mutations. Both types are used to remedy double strand breaks (DSBs), but homologous recombination is highly preferred over NHEJ because this type of editing is extremely error prone. It can delete or add genetic information and cause chromosomal translocations.

Modification of damaged DNA seems to be an understudied subject, there is much to understand on the restoration of DNA damage, repair and DNA methylation. Genomic DNA can be modified by methylation but much of it is affected on a gene when silenced. When epigenetic modification has been implicated with cancer and aging it causes DNA methylation to also have an impact on the double strand of DNA analysis. Modification as such provoke deteriorating changes like aging found in multicellular organisms and DNA damage may magnify biochemical pathways that regulate a cells growth or control DNA replication with DNA repair. In the article “DNA Damage, Homology-Directed Repair, and DNA Methylation” written by Concetta Cuozzo, Antonio Porcellini, Tiziana Angrisano, et al. they hypothesize how DNA damage and gene silencing may induce a DNA double-strand break within a genome as well as when DNA methylation is induced by homologous recombination that it may somewhat mark its reparation through a DNA segment and protect its cells against any unregulated gene expression that may be followed by DNA damage. The experiments used to demonstration how gene conversion can modify methylation pattern of repaired DNA and when that occurs methylation is able to silence the recombined gene. When exploring the molecular mechanisms that link DNA damage and the silencing gene then there is an induced double strand break that can be found at a specific location or DNA sequence in where the