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PCL477H1-Lecture 6b to post - Lecture 6 overview concept of...

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Lecture 6 overview • concept of DNA inter-strand cross-links (ICLs) • cross-links produced by agents • pathways of cross-link repair • relationship to Fanconi Anemia and Hereditary Breast Cancer Susceptibility • DNA-protein cross-links caused by agents
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Basic pathways of ICL repair • error-free process dependent on homologous recombination • error-prone process dependent on translesion synthesis • increase in Rad51 and γ H2AX subnuclear foci following exposure to DNA cross-linking agents
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Error-free path (DNA replication fork) Step 1. Nucleotide Excision Repair replication fork encounters cross-link, induces DSB XPF-ERCC1 aided by RPA, unhooks cross-link Step 2. Homologous Recombination resulting intermediate is annealed to a homologous duplex and is converted to a duplex with a cross-link by recombination reaction Step 3. Nucleotide Excision Repair prior to or during resolution of recombination, the cross-link is eventually eliminated by NER
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Error-prone process of ICL repair cells have ability to tolerate DNA damage persisting in their DNA by a process known as ‘daughter-strand’ or ‘post-replicative repair’ –enables cells to synthesize daughter DNA strands despite the presence of damaged sites on the parental strands translesion synthesis: primary function is to facilitate replication past DNA lesions that block replication .. ’sloppy synthesis’ -to escape the lethal effect of blocked replication, translesion DNA synthesis allows the replication of DNA containing persistent DNA damage How? 1 . normal DNA replication fork blocked by presence of DNA lesion and polymerase released 2. a specialized translesion DNA polymerase loaded onto the site and replicates a short distance past the lesion 3. translesion polymerase is replaced by replicative DNA polymerase
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PCL477H1-Lecture 6b to post - Lecture 6 overview concept of...

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