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 DNA Repair Mechanism

Deoxyribonucleic acid (DNA) is damaged every day by a variety of factors. This damage must be repaired quickly and efficiently to sustain the integrity of the genome. Common errors include the loss of a bases resulting in apurinic/apyrimidinic (AP) sites (abasic sites); base modifications, such as alkylations or deamidations which converts cytosine, adenine and guanine to uracil, hypoxanthine and xanthine, respectively. Photodamage by uv light can generate pyrimidine dimers, such cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). Chemical agents and reactive oxygen species (ROS) can modify bases. Replication errors and base conversions can generate mismatch nucleotide pairs. Failures in normal DNA metabolism by topoisomerases and nuclease or ionizing radiation can generate single-strand and double-strand breaks. Cells have evolved a number of DNA repair mechanisms to respond to DNA damage.

In addition to DNA polymerase 3’à5’ exonuclease proof-reading at the replicating fork, mammalian cells utilize five major DNA repair pathways: Homologous recombination (HRR); Nonhomologous End Joining (NHEJ); Nucleotide Excision Repair (NER); Base Excision Repair (BER) and Mismatch repair (MMR).

MMR, NER and BER pathways are excision repair processes that depend upon complementary DNA strands to direct their replacement of excised base(s). The MMR pathway repairs mismatches and loops generated by insertions or deletions. Hereditary non-polyposis colon cancer (HNPCC) is linked to defects in genes of the MMR pathway. Mismatch repair of damaged bases is frequently mediated by the BER pathway. The BER pathway recognizes and removes incorrect or damaged bases using a family of DNA N-glycosylases that result in the formation of an apurinic/apyrimidinic (AP) site. There are two major types of BER repair mechanisms, one involves DNA polymerase beta-dependent single nucleotide repair and the other, long-patch (2-10 nucleotides) pathway, requires PCNA. Whereas, BER processes are dependent upon specific N-glycosylases to recognize mismatches or damage, the NER pathway recognizes abnormal structures and chemistry via heterodimers composed of DDB1, XPE, XPC or HR23B proteins. Defect in NER has been associated with Xeroderma pigmentosum (XP), Cockayne's syndrome (CS) and trichothiodystrophy (TTD)

Repair of double strand DNA breaks (DSB) is mediated by homologous recombination (HRR) or nonhomologous end joining (NHEJ) pathways. HRR employs one of two related but distinct mechanisms. Synthesis-dependent strand annealing (SDSA), requires RAD51, RAD52, RAD54, RAD55, RAD57 and RAD59 and requires that a single DNA strand find its complementary sequence within a double-stranded DNA. Single-strand annealing (SSA) only requires the association of two complementary strands and RAD 52 and 59. NHEJ is homologous DNA template-independent and facilitates direct modification and ligation of two DNA ends present in DSB.