Slide 1:

Topic: Molecular Basis of Inheritance - Excision repair system
Introduction to the Excision Repair System
Importance of DNA repair mechanisms
Types of DNA damage
Overview of Excision Repair System

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Nucleotide Excision Repair (NER)
Definition and purpose
Steps involved in NER
1. Recognition of DNA damage
2. Excision and removal of damaged DNA strand
3. Repair synthesis and ligation
Example of a disorder related to NER: Xeroderma pigmentosum

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Base Excision Repair (BER)
Definition and purpose
Steps involved in BER
1. DNA glycosylase recognition and base removal
2. AP endonuclease and DNA polymerase activity
Example involving BER: Repair of oxidative DNA damage

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Mismatch Repair (MMR)
Definition and purpose
Importance of MMR in maintaining genomic integrity
Steps involved in MMR
1. Mismatch recognition
2. Strand discrimination and excision
3. Resynthesis and ligation

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Photoreactivation Repair (PRE)
Definition and purpose
Role of photolyase enzyme in PRE
Light-dependent repair mechanism
Example of a organism capable of PRE: E. coli

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Homologous Recombination (HR)
Definition and purpose
Key steps involved in HR
1. DNA double-strand break formation
2. Strand invasion and pairing
3. Holliday junction formation and resolution
Example involving HR: Repair of DNA breaks during meiosis

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Non-Homologous End Joining (NHEJ)
Definition and purpose
Steps involved in NHEJ
1. DNA double-strand break recognition
2. End processing and ligation
Example of a disorder related to NHEJ: Severe combined immunodeficiency (SCID)

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Direct Repair Mechanisms
O6-Methylguanine methyltransferase (MGMT) repair mechanism
Alkyltransferases and their role in direct repair
Example involving direct repair: Removal of methyl or ethyl groups from DNA bases

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Translesion Synthesis (TLS)
Definition and purpose
How TLS bypasses DNA lesions
Error-prone nature of TLS and its significance
Example involving TLS: UV-induced DNA damage repair

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Summary of DNA Repair Mechanisms
Importance of DNA repair in maintaining genomic stability
Key mechanisms discussed: NER, BER, MMR, PRE, HR, NHEJ, Direct Repair, TLS
Role of each repair mechanism in different types of DNA damage
Application of DNA repair mechanisms in various fields, such as medicine and biotechnology

DNA Damage and Repair

DNA damage can be caused by various factors such as radiation, chemicals, and errors during DNA replication.
The human body has evolved several mechanisms to repair DNA damage and maintain genomic integrity.
DNA repair mechanisms are crucial for preventing mutations and maintaining normal cellular functions.
Failure in DNA repair mechanisms can lead to genetic disorders and increased risk of cancer.
The excision repair system is one of the major DNA repair mechanisms.

Nucleotide Excision Repair (NER)

NER is a DNA repair mechanism that deals with bulky lesions, including UV-induced pyrimidine dimers.
This repair mechanism involves several proteins, including endonucleases, helicases, and DNA polymerases.
The NER process can be divided into two sub-pathways: transcription-coupled repair (TC-NER) and global genome repair (GG-NER).
TC-NER primarily focuses on repairing DNA lesions in active genes, while GG-NER repairs lesions throughout the genome.
Xeroderma pigmentosum is a genetic disorder caused by defects in NER genes.

Base Excision Repair (BER)

BER is a DNA repair mechanism that deals with minor base damage, such as alkylation and oxidation.
The BER pathway involves recognition and removal of damaged bases by DNA glycosylases.
After base removal, AP endonucleases and DNA polymerases come into play to replace the damaged base with the correct one.
BER is essential for maintaining genomic stability and preventing mutagenesis.
Oxidative DNA damage, caused by reactive oxygen species, is repaired through BER.

Mismatch Repair (MMR)

MMR is a DNA repair mechanism that corrects errors that occur during DNA replication.
MMR is responsible for recognizing and removing mispaired bases and small insertions or deletions (indels).
Defects in MMR genes can lead to a condition called Lynch syndrome, which predisposes individuals to various types of cancer.
MMR is crucial for maintaining the fidelity of DNA replication and preventing the accumulation of mutations.
MMR also plays a role in repairing DNA damage caused by certain chemicals and drugs.

Photoreactivation Repair (PRE)

PRE is a DNA repair mechanism found in some organisms, including bacteria and plants.
PRE utilizes the enzyme photolyase, which uses light energy to repair UV-induced DNA damage, such as pyrimidine dimers.
Photolyase breaks the covalent bond between the damaged bases, restoring the DNA strand to its original state.
PRE is a direct repair mechanism that does not involve the removal or synthesis of nucleotides.
E. coli is a well-known example of an organism capable of PRE.

Homologous Recombination (HR)

HR is a DNA repair mechanism that repairs DNA double-strand breaks (DSBs) and ensures the correct alignment of homologous DNA sequences.
HR involves the exchange of DNA strands between homologous chromosomes or sister chromatids.
The RAD51 protein plays a key role in HR by facilitating strand invasion and the formation of Holliday junctions.
HR is crucial for repairing DSBs during meiosis, as it allows for genetic recombination and the generation of genetic diversity.
HR also plays a role in repairing DSBs induced by ionizing radiation.

Non-Homologous End Joining (NHEJ)

NHEJ is another DNA repair mechanism for repairing DNA double-strand breaks.
NHEJ is an error-prone repair process that directly joins the broken ends of the DNA without requiring a homologous template.
The Ku protein complex is essential for the initial recognition and binding of DNA ends in NHEJ.
NHEJ can introduce small indels or deletions at the repair site, leading to potential mutations.
Mutations in NHEJ genes can result in severe combined immunodeficiency (SCID).

Direct Repair Mechanisms

Direct repair mechanisms involve the removal of specific DNA lesions without the need for excision or synthesis steps.
One example of direct repair mechanism is the O6-Methylguanine methyltransferase (MGMT) repair system.
MGMT removes and repairs alkyl groups, such as methyl or ethyl groups, from specific DNA bases.
Direct repair mechanisms are fast and efficient, allowing for the direct reversal of specific DNA lesions.
Direct repair mechanisms are important for preventing mutations and maintaining genomic stability.

Translesion Synthesis (TLS)

TLS is a DNA repair mechanism that bypasses DNA lesions, such as bulky adducts or crosslinks.
TLS involves specialized DNA polymerases that can replicate across damaged DNA templates.
TLS is an error-prone repair pathway, as the specialized polymerases have relaxed fidelity and can introduce mutations.
Despite being error-prone, TLS is crucial for ensuring DNA replication can continue in the presence of DNA lesions.
UV-induced DNA damage is repaired through TLS in order to prevent DNA replication arrest.

Summary and Applications

DNA repair mechanisms play a vital role in maintaining genomic stability and preventing the accumulation of mutations.
The excision repair system, including NER, BER, MMR, PRE, HR, NHEJ, direct repair, and TLS, ensures the integrity of the genetic material.
Genetic disorders, such as xeroderma pigmentosum and Lynch syndrome, can result from defects in DNA repair mechanisms.
Understanding DNA repair mechanisms has important implications in various fields, including medicine, genetics, and biotechnology.
Further research in DNA repair mechanisms may lead to the development of novel therapies and interventions for diseases related to DNA damage.

Importance of DNA Repair Mechanisms

DNA repair mechanisms are crucial for maintaining genomic integrity and preventing the accumulation of mutations.
Mutations in DNA can lead to various genetic disorders and an increased risk of cancer.
Without efficient DNA repair mechanisms, genetic information could be lost or distorted during DNA replication or as a result of DNA damage.
DNA repair systems help in preserving the genetic code and ensuring its accurate transmission to future generations.
Understanding DNA repair mechanisms is essential for studying diseases related to DNA damage and developing strategies for their prevention and treatment.

Types of DNA Damage

DNA damage can occur due to various factors, including environmental agents, chemicals, radiation, and errors during DNA replication.
Types of DNA damage include:
1. Base damage: Modifications or loss of DNA bases, such as alkylation, oxidation, deamination, or depurination.
2. DNA strand breaks: Single-strand breaks (SSBs) and double-strand breaks (DSBs) can occur due to various causes.
3. Crosslinking: Covalent linkages between DNA strands can prevent proper DNA replication and transcription.
4. Bulky adducts: Large chemical modifications or lesions that distort the DNA helix, such as pyrimidine dimers induced by UV radiation.
5. Misincorporation errors: Incorrect pairing of nucleotides during DNA replication, leading to DNA mismatches.

Overview of the Excision Repair System

The excision repair system comprises several repair pathways that remove and replace damaged DNA bases or fragments.
Key repair pathways include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and direct repair.
Each pathway has specific enzymes and proteins involved in recognizing, removing, and replacing damaged DNA.
The excision repair system operates on a wide range of DNA lesions and ensures the faithful repair of DNA damage.
Defects in any of these repair pathways can have serious consequences, including genetic diseases and cancer susceptibility.

Nucleotide Excision Repair (NER)

NER is a versatile DNA repair mechanism that removes bulky DNA lesions, such as pyrimidine dimers induced by UV radiation.
The process involves several steps:
1. Recognition of DNA damage: Damage recognition proteins detect and bind to the damaged DNA region.
2. Excision and removal of damaged DNA strand: Endonucleases make incisions on both sides of the damaged region, removing a small fragment.
3. Repair synthesis and ligation: DNA polymerase synthesizes a new DNA strand using the undamaged strand as a template, followed by ligation.
NER operates in two sub-pathways: transcription-coupled repair (TC-NER) and global genome repair (GG-NER).

Example of a Disorder related to NER: Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a genetic disorder characterized by extreme sensitivity to UV radiation.
Individuals with XP have defects in NER genes, leading to an impaired ability to repair UV-induced DNA damage.
Lack of functional NER results in a high risk of developing skin cancers and other UV-related complications.
XP demonstrates the critical role of NER in protecting against DNA damage caused by environmental factors.
Early diagnosis and protection from UV radiation are essential for individuals with XP to prevent disease progression.

Base Excision Repair (BER)

BER is a DNA repair mechanism that primarily deals with small base lesions, such as alkylation or oxidative damage.
The process involves several steps:
1. DNA glycosylase recognition and base removal: Glycosylase enzymes detect and remove the damaged base, cleaving the glycosylic bond.
2. AP endonuclease and DNA polymerase activity: AP endonuclease makes an incision in the DNA backbone, followed by DNA polymerase filling the gap.
BER is critical for maintaining genomic stability by repairing damaged bases before errors occur during DNA replication.

Example Involving BER: Repair of Oxidative DNA Damage

Oxidative stress can cause DNA damage through the generation of reactive oxygen species (ROS).
Oxidative DNA damage includes the oxidation of guanine bases, leading to the formation of 8-oxoguanine lesions.
BER plays a crucial role in repairing such oxidative DNA damage by removing the damaged base and replacing it with the correct base.
Failure to repair oxidative DNA damage can lead to mutations, genomic instability, and increased risk of diseases, including cancer and neurodegenerative disorders.
BER ensures the faithful restoration of DNA integrity and the prevention of mutagenesis caused by oxidative stress.

Mismatch Repair (MMR)

MMR is a DNA repair mechanism that corrects errors that occur during DNA replication, ensuring the accuracy of DNA synthesis.
The process involves several steps:
1. Mismatch recognition: Mismatch repair proteins identify and bind to mismatches or small indels.
2. Strand discrimination and excision: The strand carrying the error is preferentially targeted for excision.
3. Resynthesis and ligation: DNA polymerase fills the gap with the correct bases, followed by ligation.
MMR is crucial for preventing the accumulation of mutations and maintaining the fidelity of DNA replication.

Example involving MMR: Repair of DNA Mismatches

DNA mismatches can occur due to errors during DNA replication or recombination.
MMR plays a key role in correcting DNA mismatches and preventing the persistence of errors in the genome.
MMR defects can result in a condition called Lynch syndrome, characterized by an increased risk of colorectal and other cancers.
The loss of MMR function leads to microsatellite instability, a hallmark of Lynch syndrome and some sporadic cancers.
Understanding MMR mechanisms provides insights into genetic instability and the development of targeted therapies for MMR-related cancers.

Summary

The excision repair system is a complex network of DNA repair mechanisms that ensure the faithful restoration of DNA integrity.
NER repairs bulky DNA lesions, such as UV-induced pyrimidine dimers, through a multistep process.
BER deals with small base damage, such as alkylation or oxidative damage, by removing and replacing damaged bases.
MMR corrects DNA mismatches that occur during DNA replication, maintaining the fidelity of the genetic code.
Defects in any of these repair mechanisms can have severe consequences, leading to genetic disorders and an increased risk of cancer.
Understanding DNA repair mechanisms is vital for studying diseases related to DNA damage and developing therapeutic interventions.