Mismatch Repair (MMR)

• Organisms are constantly exposed to endogenous (spontaneous mutations) and exogenous agents (induced mutations) that can damage DNA.
• DNA repair processes are present in both prokaryotic and eukaryotic organisms, involving various proteins.
• DNA repair regulation is closely linked to the regulation of the cell cycle.
• During the cell cycle, checkpoint mechanisms ensure DNA integrity before and after replication.
• Failures in these checkpoints may lead to the accumulation of DNA damage.

Mismatch Repair (MMR)

• MMR repairs replication errors, removing base mismatches and small insertion/deletion loops.
• The MMR mechanism is strand-specific, distinguishing between the newly synthesized strand and the template strand.
• Germ line allelic variants in MMR genes such as MLH1, MSH2, MSH6, or PMS2 can predispose individuals to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome.
• MMR defects are associated with predisposition to colorectal cancer.

Nucleotide Excision Repair (NER)

• NER repairs DNA damage induced by environmental factors like radiation and chemical mutagens.
• NER is an important mechanism for excising UV light-induced DNA damage.
• This includes two pathways: transcription-coupled NER (TC-NER), which acts on actively transcribed DNA, and global genome NER (GG-NER), which acts on the entire genome.
• Xeroderma pigmentosum is related to human pathology which have symptoms such as: Skin photosensitivity, pigmentary lesions, elevated cancer risk for skin and internal cancers, skin telangiectasia (small dilated blood vessels), ocular changes and mental retardation.
• All XP-proteins have functions in NER and in transcription (as chromatin remodeling complex).
• Allelic variants in germ cells can lead to this disease
• Cockayne syndrome (CS) is the another human pathology.
• The incidence of CS which affects 2.7 in Europe
• The Symptoms can include: mental and developmental retardation, photosensitivity, progressive sensorineural hearing loss, short stature, a typical bird like face, deep-set eyes, loss of subcutaneous fat and, premature ageing and progressive neurodegeneration.
• A defect in NER is connected to mitochondrial base excision repair (BER)
• Defective XP and CS proteins cause a defect in TCR and affect transcription.

Base Excision Repair (BER)

• BER removes damaged bases in the DNA sequence and is responsible for removing small, non-helix-distorting errors.
• It repairs oxidized bases, alkylated bases, deaminated bases, inappropriately incorporated uracil, and single-strand DNA breaks.
• BER is started by a DNA glycosylase which recognizes and removes the damaged base.
• There are two pathways: short (removes one base lesions) un long (removes 2-10 base lesions).
• Currently, no known human disease is associated with a defect in BER, which may be due to embryonic lethality.

Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ)

• Both HR and NHEJ can repair double-strand breaks (DSB).
• HR uses a homologous DNA template and is highly accurate.
• NHEJ rejoins broken ends without a template, often resulting in the loss of some nucleotides.
• NHEJ is more active in the G1 phase, while HR dominates during the S and G2 phases of the cell cycle.
• Defective repair of DSBs can lead to chromosomal instability, characterized by rearrangements and loss of chromosomes.
• A number of human syndromes are associated with defects in DSB repair, such as hereditary breast/ovarian cancer.