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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.