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DNA repair

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**DNA Damage and Sources**:
– DNA damage occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day.
– Unrepaired lesions can impede cell function and increase tumor formation risk.
– Most DNA damage affects the double helix structure by chemically modifying bases.
– Sources of damage include endogenous factors like reactive oxygen species and exogenous factors like UV radiation and mutagenic chemicals.
– Replication of damaged DNA can lead to incorporation of wrong bases, causing irreparable mutations.
– Thermal disruption can increase depurination and single-strand breaks in DNA.

**Types of DNA Damage**:
– Endogenous damage types include oxidation, alkylation, hydrolysis, bulky adduct formation, and mismatch of bases.
– Exogenous damage types include UV-B, UV-A, ionizing radiation, thermal disruption, and damage by industrial and environmental chemicals.
– DNA damage can lead to irreparable DNA damage, premature aging, and cancer.
– Examples of damage include UV damage, alkylation, X-ray damage, and oxidative damage.
– Constitutive DNA damage caused by endogenous oxidants can be detected through histone H2AX phosphorylation.

**Impact of DNA Repair**:
DNA repair processes are crucial for maintaining genome integrity.
– Failure in DNA repair processes can lead to irreparable DNA damage.
DNA repair influences cell survival, senescence, apoptosis, and tumor formation.
– Genes involved in DNA damage repair also impact life span.
– Nobel Prize in Chemistry was awarded for work on molecular mechanisms of DNA repair processes.

**DNA Repair Mechanisms**:
– Cells have evolved repair strategies to restore lost DNA information.
– Repair can use complementary DNA strands or sister chromatids as templates.
– Specific repair molecules bind to damaged DNA sites to facilitate repair.
– Direct reversal mechanisms eliminate certain DNA damage types by chemically reversing them.
– Repair pathways for double-strand breaks include NHEJ, MMEJ, and HR.

**Global Response to DNA Damage**:
– Cells exposed to damaging agents acquire multiple sites of DNA lesions and double-strand breaks.
– Stimulation signals for a global response include double-strand breaks or adducts stalling replication forks.
– The global response triggers pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis.
– Checkpoints pause the cell cycle to allow repair before division, controlled by master kinases ATM and ATR.
– The prokaryotic SOS response in bacteria is triggered by extensive DNA damage, regulated by LexA and RecA proteins.

DNA repair (Wikipedia)

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

DNA damage resulting in multiple broken chromosomes

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:

  1. an irreversible state of dormancy, known as senescence
  2. cell suicide, also known as apoptosis or programmed cell death
  3. unregulated cell division, which can lead to the formation of a tumor that is cancerous

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.

Paul Modrich talks about himself and his work in DNA repair.

The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.

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