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Horn PJ, Peterson CL. Molecular biology. Chromatin higher order folding-wrapping up transcription. Science 2002;297:1824-1827. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveals a new mechanism for colonic carcinogenesis. Nature 1993;363:558-561. 32 Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature 2004 ;432:338-341. Redon R, Ishikawa S, Fitch KR, et al, Global variation in copy number in the human genome. Nature2006;444:444--454. Reik W, Dean W, Walter J.

The mitochondrial genes lack introns and are transcribed in full length then processed to the natural products. Origins 0H and 0L are the beginning points for replication of mtDNA. - Mitochondrial protein synthesis and DNA replication are thus under nuclear regulatory control - Mitochondrial translation is bacteria-like both in its sensitivity to antibiotics that act on the ribosome, and in its use of N-form ylmethionyl-tRNA for initiation - Mitochondrial ribosomes are smaller than those found in the cytosol, and have a sedimentation coefficient of 55 S instead of the den ser 80 S sedimentation coefficient for cytosolic ribosomes or 70 S coefficient for bacterial ribosomes mtDNA Replication • mtDNA replication is an asynchronou s process, which begins at the origin of the H strand mtDNA replication is controlled by chromosomes in the nucleu s based on how many mitochondria the particular cell needs at that time - When the replication apparatu s meets the origin of the L strand, it is forced into a single-strand configuration 30 by the extending daughter H strand, and L-strand replication begins at this point RNA derived from the L-strand promoter serves as a primer for H-strand DNA replicat ion • The D-Ioop (displacement loop) is a I I23-ba se stretch of DNA, often triple-stranded, which contains sites for DNA-binding protein s that control mtDNA replication and transcription - The D-Ioop contains the promote rs for both the H- and L-strand transcripts - mtDNA replication causes the D-Ioop to move along the heavy strand as mtDNA polymera se-y produce s a complimentary replica strand • Heavy-strand DNA replication begins at the D-Ioop and proceed s in a 5'-3' direction until returning to the origin of replication • DNA polymerase y begins in the reverse direction to produce a complimentary replica of the light Principles of Clinical Molecular Biology strand when replication of the heavy strand reaches the light strand replication origin (OL) • Two identical double-strand mtDNA molecules are the result of this process • When mitochondria have enough copies of mtDNA, sufficient mitochondrial proteins, and adequate surface area, a nuclear protein may permit the mitochondrion to divide by fission into two daughter mitochondria mtDNA Damage, Mutations, and Repair • mtDNA damage - mtDNA is susceptible to insult by all the same processes that damage nuclear DNA - mtDNA is especially susceptible to insult by reactive oxygen species, which are prevalent in mitochondria • Because mtDNA is not bound to histones, it is exposed to damage caused by free oxygen radicals produced by electron transfer during oxidative phosphorylation of the respiratory chain • mtDNA also undergoes the same types of mutation as nuclear DNA including spontaneous modifications and replication errors • mtDNA mutations - The rate of mutation in mtDNA is calculated to be about 10 times greater than that of nuclear DNA - The mtDNA mutations may be either acquired or inherited - Several different mutations of mtDNA may present clinically as the same disease - Large deletions and duplications of mtDNA increase with age • This may account for some aging processes in oxygen-dependent organs, such as brain, kidney, muscle, and heart • Mutant electron transfer proteins may release more oxygen-free radicals into the mitochondrial matrix, accelerating the aging process in some cases of Alzheimer's and coronary artery disease - There are hypervariable segments (HVI and HV2) located at base 57-372 and base 16,024-16,383, respectively.

14. Diagrammatic repre sentation of an interstitial deletion. S/ I000) • Depends on amount of material deleted • Difficult to make phenotype/karyotype correlations - Sex chromosome • reX), r(Y) 4p Deletion • Deletion (4p)- general Wolf-Hirschhorn syndrome - - Often unable to complete mitotic division s Deletion-short arm of chromosome 4 (p 16) - Leads to mosaici sm Frequency-1I4S,00D-lIS0,000 - Loss of ring First reported-Wolf et al.