Biology of Cancer - Tunghai University：东海大学的癌症生物学.ppt

Figure 12.6 (part 2 of 2) The Biology of Cancer (? Garland Science 2007) Figure 12.7 The Biology of Cancer (? Garland Science 2007) D400A mutation: change of the #400 a.a. from D (aspartic acid) to A (alanine) in the proofreading domain of DNA polymerase δ Deaths of the mutant homozygotes were all due to malignancies. Proofreading by DNA polymerase δ and cancer incidence in mice Figure 12.8c The Biology of Cancer (? Garland Science 2007) Mismatch repair (MMR) enzymes detect mistakes in newly synthesized DNA strand Two components of the MMR apparatus, MutS and MutL, collaborate to remove mismatched DNA: MutS scans the DNA for mismatches. MutL then scans the DNA for single-strand nicks, which identify the strand that has recently been synthesized. The action of mismatch repair system is critical in regions of the DNA that carry repeated sequences (microsatellite sequence). Mononucleotide repeats: AAAAAAA Dinucleotide repeats: AGAGAGAG Repeats of greater sequence complexity Figure 12.8a The Biology of Cancer (? Garland Science 2007) A defective MMR system will result in the expansion or shrinkage of microsatellite sequences, known as microsatellite instability (MIN). Figure 12.28 The Biology of Cancer (? Garland Science 2007) A TGF-β receptor gene affected by microsatellite instability The type II TGF-β receptor is frequently inactivated in human colon cancers, which carry defects in mismatch repair genes and exhibit microsatellite instability (MIN). 10 A’s 8 A’s Cells deploy a wide variety of enzymes to accomplish the very challenging task of restoring normal DNA structure. Mismatch repair (MMR) enzymes largely focused on detecting nucleotides of normal structure that have been incorporated into the wrong positions. Other repair mechanisms detect nucleotides of abnormal chemical structure. 1. dealkylating enzymes 2. base-excision repair (BER) 3. nucleotide-excision repair (NER) 4. error-pr