Cell cycle, implications in apoptosis, cancer and DNA damage
With this work it is intended to provide a general idea of the complexity of the cell cycle, due to the numerous regulations that take place in it. The phases of the same are briefly explained, the implications in apoptosis and cancer, and the response to damage to the DNA. Subsequently, the great precision of the cycle is detailed in the different control points. Finally, some of the current investigations related to several diseases are reported.
Abbreviations
ATM – Serine atm protein/treonine kinase (Telangiectasia mutated ataxia)
ATR – ATR SERINA/TREONINA QUINASA (ATAXIA TELANGIETTASIA AND RAD3 RELATED)
CDK-Cycline-dependent kinase (cyclin-dependent kinase)
DBS-Double chain breakage damage (Double-Strand Break)
MAPK-Mitogen activated kinase protein (mythogen-activity Kinase protein)
MRN-MRE11-RAD51-NBS1 COMPLEX
PRB/ RB – Gen/ Retinoblastoma Protein
Introduction
In 2001, for their discoveries about the regulatory keys of the cell cycle, British scientists Timothy Hunt, Paul Nurse, and the American Leland Hartwell won the Nobel Prize in Medicine. Thanks to their investigations, the control mechanism of cell division processes is better known and some of the key molecules that regulate them were identified.
In addition, the conceptual bases of the cell cycle that can be summarized in:
- The cell cycle is a sequence of temporarily organized events.
- Each of them begins with the completion of the previous one, being a process regulated by a series of controls throughout the cycle.
- There are signs that relate events.
- Some events are limiting to the progression of the cycle.
The cell cycle can be defined as an orderly set of processes in which cell growth occurs, cell components double, and a division into daughter cells. It begins with the generation of a new cell, and ends at the time that said cell originates new daughter cells.
In eukaryotes, there are two phases of growth: G1 and G2 (their names come from the word in English: GAP, interval), which are periods in which the cells obtain mass, integrate growth factors, organize a replicated genome and prepare and prepare For chromosomal segregation. DNA replication is limited to a discreet synthesis or S phase, and chromosomal segregation is carried out in phase M.
This complex mechanism requires great precision at the control points, which monitor the order, integrity and faithfulness of the main events of the cell cycle. In addition, they prevent genetic alterations from spreading to later generations, providing a barrier to cancer development.
Many of these mechanisms have been widely studied in simple organisms such as yeasts, because they have an ancient origin and are highly preserved. On the other hand, others have evolved in higher organisms, controlling alternative cellular destinations with a significant impact on tumor suppression.
Cell cycle phases
The cell cycle is divided into stages, through which the cell passes from a cell division to the next; duplicating its content and then dividing into two.
The duration of the cell cycle differs according to the species and the tissues to which the cell belongs, also depending on external factors such as temperature or nutrients available. The greatest time variations occur in the G1 phase. For example, a division mammal cells take approximately 24 hours, however, in Drosophila Melanogaster (fruit fly) the duration is 8 hours. In some bacteria such as e.coli, the cell cycle is completed in just 3 minutes.
The cell cycle is divided into two phases:
- The preparatory or interface period, which is subdivided into: phase G1, phase S and phase G2. During this, the degree of condensation of genetic material and DNA content varies, without modifying the number of chromosomes. It can last days, weeks or more time, depending on the cell lineage and the prevailing environmental or physiological conditions. The first phase of the cell cycle is the G1, in which cell growth with protein and RNA synthesis occurs, as a result of the expression of genes that encode the proteins responsible for its phenotype. In addition, some organelles double. Its duration is 6 to 12 hours, in which it doubles its size and mass. At the end of this phase, there is a restriction point R, in which damaged DNA is repaired, which will be explained later. The intersafe continues with the S phase, in which the synthesis of the DNA occurs, the chromosomes double and form two identical chromatids. At the same time, nuclear proteins double. Its duration is approximately half of the complete cell cycle in mammals (10-12 hours). Once the chromosomes have doubled, the cell enters a second period of growth, the G2 phase, in which the synthesis of protein and RNA continues, and prepares for cell division. It ends when chromatin begins to condense at the beginning of mitosis, being its duration of 3-4 hours.
- The mitotic phase or M phase in which the division occurs in the two identical daughter cells. It is divided into mitosis or meiosis, in which duplicate chromosomes are divided into two nuclei making a distribution of nuclear genetic material, for which the necessary structures are assembled; And in cytocinesis, where the entire cell is divided into two daughter cells, that is, the cytoplasm division. In mammals it usually lasts from 30 minutes to 1 hour. In the myitosis process, each daughter cell receives a complete game of chromosomes (diploid cells) and is genetically identical to the parent cell. There are several differences in meiosis, since a single copy of each chromosome (haploid cells) and half of the cytoplasm is distributed to each of the two daughter cells.
Phase G0
It starts with rest cells, which are found in the G0 phase, these have to be stimulated by growth factors to enter the cell cycle, since this stage is out of the cycle. The cells that are in the G0 phase are found in a vegetative state, can be: quiescent that comes from the G1 phase and can remain in an inactive or rest state for an indeterminate period of time, while new cells are not needed , since they can return to the cell cycle. They can also be senescent cells that cannot return to the cell cycle, they ensure that damaged or defective DNA sequences do not go to daughter cells.
This phase is related to the post-midotic state. Some types of cells, such as skeletal neurons or muscle cells, when reaching maturity, enter the G0 phase, and perform their functions for the rest of the organism’s life.
Liver cells are also found in the G0 phase, and are divided only once or twice a year or in the face of stimuli as an injury in the tissue. This does not imply inactivity, since hepatocytes are one of the most active metabolically active cells.
This fact has led to biotechnological studies, such as Liu, D.Z and Ander, B. P., At the University of California. Important applications have been found, because if a neuron, instead of inducing his cell death, he is able to remain in G0 the neurodegenerative diseases could be less harmful. Or a cancerous cell could be induced to G0 so that it will not be replicated. However, this will only be possible if the signaling mechanisms are different in NPCs that divide into the adult brain, but cognitive damage could be caused. This is because, inhibition strategies are not specific to cells because they also block the proliferation of important brain cells, harming adult brain neurogenesis.
Apoptosis and cancer
In normal tissues there is a balance between the generation of new cells and the loss of cells through programmed death or apoptosis, which is a highly controlled process. The cell damaged over time are eliminated and, thanks to this method, they can be renewed. Apoptosis is equivalent to a “self-destruction button”, with which the number of neurons can be regulated during the development of the nervous system, eliminate lymphocytes that do not work properly or can “mold” the shapes of a developing organ, eliminating cells Specific.
Apoptosis helps prevent cancer development by eliminating any strongly damaged cell. Because, if this process does not occur, damaged cells can survive, transforming into cancer cells, which have escaped normal control of division and cell death, since they begin to proliferate in a uncontrolled way. This can lead to the formation of a cell mass called tumor.
DNA damage
DNA is damaged when its sequence is altered or changed, action caused by physical, chemical or biological agents known as mutagens. They can be endogenous agents, generated by metabolism itself, or exogenous, from abroad. Depending on the type of mutagen (alkylating agents, free radicals, ultraviolet light, X -rays, etc.), there are different damages.
Oxidative lesions can occur, caused for example by free radicals or hydrogen peroxide, being the most dangerous and difficult to repair those that produce double chain breakage damage (DBS), as they cause chromosomal translocations, specific mutations, insertions and deletions. This damage is potentially lethal for cells, so they must be quickly recognized and repaired. For which, there are cellular mechanisms that recognize DBSS. At control points, proteins are able to delay the progress of the cell cycle to facilitate repair.
Thanks to the study of these breaks, it has been possible Pi3-Kinase (Pikk) proteins.
The Pikk family includes different members with a common structure: Atm, Dnapkcs, MTOR and HSMG1; All of them related to signaling processes after cell stress.
The double chain break is the signal that activates the ATM and DNA-PKCD proteins and the ATR responds to a simple chain breakage. ATM is quickly recruited to the place where DSB has occurred, suffers autophosphate and separates in monomers. The Mre11-Rad51-NBS1 (MRN) complex is also recruited, which is the primary sensor, and then becomes a phosphorylated Atm substrate.
ATR joins in a late phase and maintains phosphorylated specific substrates, this redundancy of phosphorylation, adds greater complexity to the response. In addition, ATR also responds to DNA damage to those who do not respond ATM, because some of its substrates are dephosphorylated, for example to UV radiation, blocked replication forks and hypoxia.
Regulation
The cell cycle is highly regulated at different points and, also, by various factors with which it interacts, such as lack of nutrients, cell size, temperature changes, pH changes, etc. These factors can cause the decrease in speed or growth detention and cell division, ensuring that cells are not divided into unfavorable conditions.
Cell proliferation occurs in a controlled manner according to the general needs of the agency. Some cells are divided at high speed; nerve cells, when maturing they lose the ability to divide; The hepatic, retain their division capacity, but do not use it, they only divide if part of the liver is eliminated, until the liver reaches its normal size.
Cell size
Cell size is critical to regulate the amount of genetic and biosynthetic material, nutrient distribution and oŕgano function. The cell must double its content exactly before division.
It has been observed that the size of daughter cells affects the progression of the cycle, for example, large cells accelerate progression through G1 and/or G2, and small delay the exit of growth phases. Because of this, the existence of control points in G1 and G2 of cell size has been proposed. However, the location of these control points and how they affect the change of size, varies greatly in the different species and types of cells.
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