Summary Robbins CHAPTER 1 The Cell as a Unit of Health and Disease

ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE 10TH EDITION

CHAPTER 1 The Cell as a Unit of Health and Disease

Prepared by: Omid J. Siahmard

THE GENOME

Noncoding DNA

 Within the human genome, only 20,000 genes encode proteins constituting just 1.5% of
the genome.
 Five Major Classes of Functional Non-Protein-Coding Sequences in the Human Genome
o Promoter and enhancer regions
 Provide binding sites for transcription factors
o Binding sites for factors that organize and maintain higher order chromatin
structures
o Noncoding regulatory RNA
 Not translated BUT regulate gene expression
 Examples: micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs)
o Mobile Genetic Elements
 Example: transposons; “jumping genes” move around the genome during
evolution resulting in variabilities
o Telomeres and Centromeres (special structural regions of DNA)
 Satellite DNA
 Major component of centromeres
 Repeating sequences
 Associated with spindle apparatus attachment
 Maintains the dense, tightly packed organization of heterochromatin
 The two most common forms of DNA variation in the human genome are single nucleotide
polymorphisms (SNPs) and copy number variations (CNVs)
o SNPs
 Variants at single nucleotide positions and are almost always biallelic
 Can occur across the genome (introns, exons, intergenic regions)
 Roughly 1% of SNPs occur in coding regions
o CNVs
 Form of genetic variation consisting of different numbers of large contiguous
stretches of DNA
 Approximately 50% of CNVs involve gene-coding sequences
 Epigenetics – Heritable changes in gene expression that are not caused by variations in
DNA sequence.

Histone Organization (Epigenetic factors)

 Nucleosomes consist of DNA segments 147 bp long that are wrapped around a central core
structure of highly conserved molecular weight proteins called histones.
 At the light microscopic level, nuclear chromatin is recognizable as:
o Heterochromatin: cytochemically dense and transcriptionally inactive
o Euchromatin: Disperse and transcriptionally active
 Histone methylation
o Lysines and arginines can be methylated by specific writer enzymes
o Methylation of histone lysine can lead to either transcriptional activation or
repression.
 Histone acetylation

, o Lysine residues are acetylated by HATs (histone acetyltransferases)
 Resulting in opening of the chromatin and transcription
o Histone deacetylases (HDACs)
 Reverses action of HATs; leads to chromatin condensation and inactivation.
 Histone phosphorylation
o Serine residues can be modified by phosphorylation
o May result in either activation of inactivation of chromatins
 DNA Methylation
o Typically results in transcriptional silencing

Micro-RNA and Long Noncoding RNA

 Transcribed but not translated
 Important role in gene regulation
 Micro-RNA
o miRNAs do not encode proteins
o they modulate translation of target mRNAs
o Does posttranscriptional silencing
o miRNA transcription -> primary miRNA -> pre-miRNA -> exported out of the
nucleus -> trimmed by cytoplasmic Dicer enzyme -> mature double-stranded
miRNAs -> unwinds and incorporate with RNA-induces silencing complexes (RISC)
-> posttranscriptional silencing
 Long Noncoding RNA
o lncRNAs can bind to chromatin and restrict RNA polymerase from accessing coding
genes within that region
o Example: XIST
 Transcribed from X chromosome
 Essential role in X chromosome inactivation
 Excaped X inactivation but forms a repressive cloak on the X chromosome
resulting in gene silencing
o Can facilitate: Gene activation, gene suppression, chromatin modification, assembly
of protein complexes

CELLULAR HOUSEKEEPING

 Maintains normal functioning and intracellular homeostasis
 Rough endoplasmic reticulum (RER) and Golgi apparatus
o Assemble new protein destines for the plasma membrane or secretion
 Free ribosomes
o Synthesize proteins intended for the cytosol
 Breakdown of molecules, proteins, and organelles takes place at three different sites:
o Proteasomes
 Disposal complexes that degrade denatured or otherwise “tagged” cytosolic
proteins
o Lysosomes
 Site of senescent intracellular organelle breakdown (autophagy) and where
phagocytosed microbes are killed and catabolized
o Peroxisomes
 Contain catalase, peroxidase, and other oxidative enzymes
 Contribute in the breaking down of very long-chain fatty acides, generating
hydrogen peroxide in the process
 Endosomal vesicles – shuttle internalized material to the appropriate intracellular sites
 Cytoskeleton