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Biotechnology and DNA repair: focus on the PARP1 protein

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Biotechnology and DNA repair: focus on the PARP1 protein

An unprecedented damage-repair model, framing the molecular mechanism that is activated after DNA double-strand breakage, sheds new light on targeted anti-tumor therapies.

In humans, factors such as pollutants present in the environment, radiation and chemical substances, as well as errors during its replication process (responsible for mutations that are very harmful to health) determine a series of damage to DNA, with negative impacts on functions cell phones, on development of diseases and on the increase of cancer risk.

To be precise, the DNA damage it is given by “changes or disruptions that occur in its molecule” and it can be of different types, including that caused by breakages affecting its filaments. More specifically, in DNA single-strand breaks (o SSBfrom the English Single-Strand Breaks) only one strand is cut, while in double strand breaks (o DSBfrom the English Double-Strand Breaks) are both cut.

This last type of damage is considered the most serious, since «DNA breaks in two.” thus interrupting its replication e «activating processes that can lead to cell death” [fonte: “DNA Damage and DNA Repair: Types and Mechanism” – Microbe Notes].

However, “to ensure the integrity of their genomes, cells have evolved to develop DNA repair mechanisms». In this regard, research in the last decade in the field of biotechnology has discovered that, in these mechanisms, the so-called “PARP1 protein” (note as DNA damage “sensor”.), both in reference to single-strand breaks and double-strand breaks, «coating the filaments and acting as a shield» [fonte: “PARP1” – ScienceDirect].

The way in which broken DNA strands are held together, preventing them from separating irremediably, was recently studied by the Dresden Polytechnic, which, in its work, started from the known knowledge on the role of the proteins PARP1 and FUS. The hypothesis – subsequently validated by a biochemical test in a test tube – from which the research work began, sees the PARP1 molecules aggregating to give consistency to a sticky material, capable of holding the ends of the two DNA strands together, thanks also to the “softening” action of the FUS protein. What the authors highlight offers new material for international research on oncological therapies that aim to destroy only tumor cells (in this case, those enveloped in PARP1 superglue), saving healthy ones, with enormous benefits for the patient.

Biotechnology and DNA repair: the PARP1-directed protein cord

A group of scientists directed by the Biotechnology Center of the Polytechnic University of Dresden, in Germany, recently expressed its opinion on the DNA repair activities of the PARP1 protein. In “PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends”, a study published in the February 2024 issue of the scientific journal Cell, the team focuses, in particular, on breakage of DNA into two pieces and on the behavior of our cells «nell’make sure the broken wires do not separate and can be reconnected».

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The “how” this happens, «has remained, until now, a mystery» observe the authors. And they underline:

«DNA double-strand breaks are repaired at their sites. To date, however, it is still not clear how these sites are assembled and how the separation of the broken DNA is prevented»

What we know is that the PARP1 protein acts as an “first aid” at the accident site: «…its job is to travel along the DNA and patrol it, constantly looking for damage to repair. Once a double-strand break is detected, the alarm goes off to summon the repair proteins».

The known mechanism is that of protecting – isolating it – the exact point of the double strand breakagecompared to the rest of the environment. So, upon arriving on site, PARP1 first delimits the area, to allow the molecular repair team to carry out their work in a safe space.

A superglue made of proteins to rejoin the broken strands of DNA

One of the repair proteins called upon by PARP1 is theFused Protein in Sarcoma” – also called FUSfrom the English “Fused in Sarcoma” – known to be a “binding” protein, implicated in maintenance of DNA integrity. [fonte: “Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA“ – National Library of Medicine].

Even regarding the function of FUS in the dynamics of double-strand break repair – explains the study team on the subject of biotechnology and DNA repair – there is not much information. We only know that it is recruited to damaged DNA sites.

The starting hypothesis formulated by the authors is that the individual PARP1 molecules are able to detect the breakage of the double strand of DNA and, subsequently, connect to each other to give consistency to a sort of “drop” than what they – themselves – have defined “underwater superglue”sticky to the point of preventing the separation of the two ends of each of the filaments.

«We call this glue “condensed”, a mass of tightly interconnected proteins and DNA molecules, isolated from the rest of the cell. This glue would form a special healing zone»

highlights the research group. And, in all this, what role would the FUS protein have? «We could demonstrate that the FUS acts as a lubricant per soften the glue, so that the repair proteins do not find a wall in front and can easily enter inside the condensate to complete their task».

The researchers consider it an example of «collective protein behavior», in which each protein plays its part, but all with the common goal of working together to reverse – together – DNA damage.

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Biotechnology and DNA repair: test tube scenario of the hypothesized mechanism

To validate the hypotheses formulated, scientists from the Biotechnology Center of the Technical University of Dresden recreated the damage scenario in a controllable, cell-free environment such as that of biochemical test in test tubewhich allowed them to gain unprecedented insights into the regulation of the DNA double-strand break repair mechanism.

The study first demonstrated that double-strand break sites form across the co-condensation of proteins and DNA molecules.

«The co-condensates exert mechanical forces to hold the ends of the broken DNA together and become enzymatically active for the synthesis of the PARP1 protein. E the FUS protein stabilizes broken DNA ends against separationrevealing an order of events that prepares broken DNA for repair» the team points out. More in detail, “separation of DNA ends is prevented by bidirectional condensation forces exerted by intermolecular interactions».

The results obtained from the test tube representation of the hypothesized molecular mechanism provide a DNA damage repair paradigm through activation of the PARP1 protein. The authors conclude:

«We note a remarkable correspondence between the behavior of PARP1 and other DNA damage factors in vitro and in cells. This implies that the interactions identified in our biochemical tests closely resemble those that operate in cells. Notably, this congruence was observed for both large and smaller irradiation-induced DNA lesions.»

The work of the German University, however, only examines certain types of DNA double-strand breaks, which is why – in the future – they will be necessary further investigations to understand whether other classes of DNA damage present the same dynamics of the PARP1 protein or another behavior.

Glimpses of Futures

The value of the study conducted by the Biotechnology Center of the Dresden Polytechnic on the subject of DNA repair does not only lie in having reconstructed the crucial task of the PARP1 protein after the breakage of the DNA double strand. It also marks an important milestone in cancer research, with a particular focus on targeted oncological therapies.

«Because of its role in DNA damage repair, PARP1 is already a target of approved cancer treatments. Inhibition of PARP1 selectively kills tumor cells. Our work reveals the molecular and physical basis of why these cancer therapies are so successful» remarks the team.

Using the STEPS matrix, We are now trying to anticipate future scenarios, analyzing the impacts that the evolution of the DNA damage-repair model, intuited and reconstructed in a test tube by German researchers, could have from a social, technological, economic, political and sustainability point of view.

S – SOCIAL: the data emerging from this study help to better understand «the broader role of DNA damage repair in tumors, thus supporting the strategy for targeted cancer therapy, the potential of which is to only suppress the DNA damage response of tumor cells, without affecting healthy ones» [fonte: “DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy” – Nature]. For cancer patients, this translates into a reduction in side effects, typical of conventional therapies. And, in a future scenario, their complete elimination, with positive impacts from a psychological perspective and the timing of resumption of activities.

T – TECHNOLOGICAL: the intuitions (later validated by the biochemical test in a test tube) that guided the Dresden biotechnologists led to the definition of a DNA damage-repair model according to which anti-tumor therapy would damage the PARP1 superglue, «to the point of “blocking” it on the DNA and making it an obstacle to the replication mechanism of tumor cells, pushing them to commit suicide». In the future, new research and new biotech techniques are needed to confirm this scheme and delve deeper into its steps, leading, one day, to abandoning the test tube to move on to in vivo tests.

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E – ECONOMIC: targeted cancer therapies – which the research described supports – adapt to the patient’s genetic profile, in line with their cells’ repair response to DNA damage. They therefore require preliminary genetic tests and molecular diagnostic tests, the cost of which is quite high, posing some critical issues related to the oncology expenditure supported by the National Health System. Just to mention a few numbers, in the EU the overall economic impact of oncological diseases is estimated to exceed 100 billion euros per year. Hence the urgency of defining increasingly specific financial instruments to support member countries.

P – POLITICAL: in the future, the possible evolution of targeted oncological therapies, based on the inhibition of PARP1 superglue, will require increasingly attentive policies to guarantee economic-financial support through concrete actions. The European Plan to fight cancer, presented by the European Commission in 2021, goes in this direction, promoting, in addition to sustainable prevention and more effective early diagnosis, equal access to the latest generation diagnostics and genetic-based treatments.

S – SUSTAINABILITY: in a future scenario in which targeted anticancer therapies, adhering to the inhibition mechanism of the PARP1 superglue, pass all tests and are approved, the problem of their social sustainability will arise, given by equal access to their use and by the reduction of health inequalities. The latter, in the specific case of our country, arise with the approval of the bill on the differentiated autonomy of the Regions of 23 January 2024, which establishes “health regionalism”, with the risk of not seeing guaranteed in a homogeneous manner, in all regions, diagnostic tests and treatments for cancer patients.

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