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March 24, 2016

A heat shock (or stress) is one of the most studied factors of a cell stress, though its delayed effects remain largely unknown. According to two articles by Russian scientists (an article from the 1st of July 2015 in Nucleic Acids Research was continued with a February article in Cell Cycle, a heat shock mostly influences the cells at an early synthetic phase, and not only temporarily stops the DNA replication, but also causes some more serious consequences. According to one of the authors, Sergey Razin, head of the molecular biology department of the Lomonosov Moscow State University, the results of the research may help developing new methods for curing cancer.

When a cell breaks forks

Our cell just as we ourselves can be subject to stress, but unlike ours, cellular stress is caused by heat, cold, lack of oxygen, changes in acidity level, inflammation, infection or toxins, irradiation with x-rays or ultraviolet light.

'We have demonstrated that an acute heat stress triggers development of cellular senescence in normal and cancer human cells that are at an early S-phase of a cell cycle. We identified the mechanism by which a heat stress induces cellular senescence. The reason for a heat stress-induced senescence is persistent DNA damage response, connected with a formation of difficult-to-repair double-stranded DNA breaks,' tells Sergey Razin, head of the Molecular Biology Department, the Lomonosov Moscow State University, and head of the laboratory, Institute of Gene Biology, Russian Academy of Science, PhD in biology, Corresponding Member of the Russian Academy of Sciences (RAS) and co-author of both articles.

Using a wide range of methods Russian scientists from MSU and Institute of Gene Biology, RAS, showed that a cell under stress is able to 'break forks'. The forks here, though, are not a metal flatware: that is how the structures in double-stranded DNA are called when the double helix it is split so that each strand could serve as a template for the synthesis of a new DNA chain (so proceeds the DNA doubling). This duplication of DNA is based on a complementary principle stating that each nucleotide -- a 'letter' of a DNA being synthesized-- is selected based on the type of nucleodide present in this position in the template chain.

It was discovered that a heat shock suppresses the activity of topoisomerase I that relaxes a DNA during replication by cutting one of the two strands. That leads to breaks in one strand, and when a replication fork reaches the same spot, the other strand becomes also broken. As the special 'repairing' proteins consider similar parts of the second strand, with them both damaged, a DNA is extremely difficult to repair.

One more exciting outcome of this study, according to Sergey Razin, is 'a demonstration that genetically identical cells may differ dramatically both in resistance to exogenous stress factors and a type reaction to various stresses.'

Just as a stress influences a person differently during their lifetime, a damage that cell would suffer from life's troubles depends on its stage in the cell cycle. So, they are worth considering precisely.

Childhood, adolescence, youth, mitosis

The lifetime of each somatic (other than reproductive) cells of our body is varying largely depending on its peculiarities: erythrocytes (biconcave red blood cells) live about 120 days, epithelial cells lining the inside of the intestine -- about 1-2 days, while neurons and striated muscle tissue cells -- just as long as an organism. Fast-living cells are constantly dividing to provide a sufficient replacement, while long-livers never or almost never do.

With all that diversity, somatic cells (not only in human, but also in animals and plants) may be said to have four phases of a cell cycle: G1, S, G2 (together making in interphase), and mitosis (a division phase, which results in building two absolutely similar daughter cells, inheriting a chromatid -- one half of a mother's chromosome). During the G1, pre-synthetic phase, a cell growth takes place, and the cell is prepared for DNA doubling (replication): having received a half of a chromosome, a cell needs to complete it by itself, in order to pass it to the next generation. The doubling (a synthesis, hence the name -- synthetic phase) happens in the S-phase. Avoidance of mistakes in copying genetic information is under a strict control of the p53 protein: when a DNA is damaged it boosts production of the p21 protein, which is connected to complex of cyclin and cyclin-dependent kinases, responsible for initiating the next stage of the cycle. This delays the start of the S-phase for repair enzymes to have time to fix damage. Then follows the G2 phase during which a cell grows and prepares itself to a future division. At this stage a DNA is subject again to a mandatory 'inspection', and then mitosis starts. After mitosis each of the 'newborn' cells goes through G1 stage, and a cycle repeats.

Breaking away from Sa?sāra

Some cells leave a row of divisions, hovering in the G0 phase (which, in a first approximation, is G1 phase extended to an eternity)). But for the remaining ones the 'wheel of becoming' also is not endless: after approximately 52 divisions (the so-called Hayflick limit, named after Leonard Hayflick who discovered it in 1961) a cell is aging, becoming indifferent to a 'secular mess', leaves the wheel of life, stops mitosis, and eventually dies. But when a DNA in a cell is damaged so that it is hard to repair, it appears reasonable to withdraw this cell from the cycleinstead of copying a damaged genetic code, creating generations of mutants, which can finally lead to inflammations and development of cancer tumors.

'Basing on the cell reaction to a heat stress, we formulated a model of a cell senescence induction, which is true to many DNA-damaging agents. According to this model, any DNA damage (single- or double-stranded break) happening at an early S-phase may lead to initiation of a cell senescence program' -- tells Sergey Razin.

The value of the research in the area is ambiguous. On the one hand, scientists aspire to prevent aging of normal cells: to help them resist stress and function as long as possible (within their natural functions, of course). On the other hand, a controlled start of cellular senescence helps those gone 'off the rails' of a genetic program vigorously dividing cancer cells find their ways to a nirvana. That is why finding a suitable 'Occam's razor', that would force defective cells to stop dividing and multiplying entities, is vital while curing oncologic diseases.

'Disclosure of the mechanisms of the cellular senescence induced by a mild genotoxic (DNA-damaging) stress appears to be important both for understanding the reasons and mechanisms of a organismal aging, and a better understanding of a cell response variability to exogenous and endogenous stress factors. This research also casts light to multiple previously unattended effects of DNA-damaging agents (for instance, camptothecin) which are often used in a tumor therapy. Theoretically, the results of the study may lay a basis to an optimization of existing protocols of simultaneous application of hyperthermia and chemotherapeutic agents for curing oncologic diseases', Sergey Razin concludes.

Lomonosov Moscow State University

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