Transcript lecture 7
Mechanisms of DNA repair Dr.Aida Fadhel Biawi 2014 Base excision 1- It is responsible primarily for removing small, nonhelix-distorting base lesions caused by oxidation, alkylation, hydrolysis, or deamination. 2- BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch (where a single nucleotide is replaced) or long-patch BER (where 2-10 new nucleotides are synthesized). Defects in a variety of DNA repair pathways lead to cancer predisposition, and BER appears to follow this pattern. Deletion of BER genes increases the mutation rate in a variety of organisms, predicting that loss of BER could contribute to the development of cancer. Indeed, somatic mutations in Pol β have been found in 30% of human cancers like colon cancer. DNA repair by base excision. * Nucleotide excision repair (NER), which recognizes bulky, helixdistorting lesions Xeroderma pigmentosum (Xeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient. In E. coli, proteins UvrA, UvrB, and UvrC are involved in removing the damaged nucleotides (e.g., the dimer induced by UV light). The gap is then filled by DNA polymerase I and DNA ligase. DNA repair by nucleotide excision * Mismatch repair MMR , which corrects errors of DNA replication and recombination that result in mispaired (but undamaged) nucleotides . Also, Mutations in the human of the Mut proteins affect genomic stability, which is implicated in most human cancers. Specifically colorectal cancers are attributed to mutations in the genes encoding the MutS and MutL, like Muir-Torre Syndrome (MTS) which is associated with skin tumors. Muir-Torre Syndrome (Muir–Torre syndrome (MTS) is an inherited cancer syndrome, that is develop cancers of the colon, breast, and genitourinary tract, and skin lesions,. DNA repair and Aging Aging can be defined as progressive functional decline and increasing mortality over time. - DNA damage accumulates with age, and DNA repair defects can cause phenotypes resembling premature aging. DNA repair and Cancer Therapy The DNA repair teams (green) in a cancer cell can undo the damage caused by drugs or radiation therapy, enabling cells to survive. Repair inhibitors (blue) are designed to block repairs so cancer's defenses fail.