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1
• Cell maintains genome integrity and promotes faithful genome
propagation.
• It does so by
– Coordinated DNA replication
...
Genetic instability can also have a specialized role in the generation of
variability in developmentally regulated process...
Chromosomal instability (CIN)
• Chromosomal instability (CIN) refers to changes in
chromosome structure and number that le...
Reasons for genetic instability
• Replication as a source of DNA breaks
• Suppressors — proteins that act to prevent GIN
•...
Replication as a source of DNA breaks
• DNA is most vulnerable during the S phase of the cell cycle.
• Replisome must over...
Suppressors of genome instability
• Suppressor is a gene or protein that acts in trans to preserve
genomic integrity.
• p5...
DNA damage is caused
by heat, radiation, or
chemicals.
p53 allows cells
with repaired
DNA to divide.
Step 1
DNA damage is
...
•Ataxia telangiectasia mutated (ATM) - a serine/threonine protein
kinase that is recruited and activated by DNA double-str...
10
Fragile sites
• Fragile sites are DNA sequences that show gaps and breaks
following partial inhibition of DNA synthesis.
•...
DNA secondary structures at DNA repeats
• Fragile sites are usually associated with trinucleotide repeats
(TNRs) of the ty...
Models of double-stranded break formation at fragile sites
13
Transcription-associated instability
• Transcription stimulates
– recombination i.e. transcription associated recombinatio...
15
Hairpin and R Loop formation during transcription
Telomere shortening
16
•During the cell division, genomic instability is minimized by four
major mechanisms
High fidelity DNA replication in S p...
18
During the cell division
cycle , 4 major
mechanisms are
involved in maintaining
genomic stability :
1.Fidelity of DNA
r...
Tumor – is a condition where there is abnormal cellular growth thus
forming a lesion or in most cases, a lump in some part...
20
• Benign tumors
generally do not
spread by
invasion or
metastasis
• Malignant
tumors are
capable of
spreading by
invasi...
21
Cellular Basis of Cancer
• Cancer is a collection of diseases
characterized by abnormal and
uncontrolled growth
• Cance...
Normal cells vs. Cancer cells
Normal cell proliferation Cancer cell proliferation
Density-dependent inhibition Can grow on...
Oncogene - genetic material that carries the ability to induce cancer.
23
Development of Cancer
• Cancer develops only after a cell experiences ~6 key
mutations (“hits”)
– unlimited growth
• turn ...
Genomic instability is a key hallmark of malignancy
•Cancer is caused by successive gene mutations that amount to
confer m...
Genomic instability might be a potential driving force in the
transformation of normal stem cells into cancer cells.
Genom...
27
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Genomic instability and Cancer

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Relation between genomic instability and cancer

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Genomic instability and Cancer

  1. 1. 1
  2. 2. • Cell maintains genome integrity and promotes faithful genome propagation. • It does so by – Coordinated DNA replication – DNA-damage sensing and repair – Cell-cycle checkpoints • Most checkpoint factors are evolutionarily conserved and many are tumour suppressors INTRODUCTION •Genetic instability refers to a range of genetic alterations from point mutations to chromosome rearrangements. •Can be divided into classes according to the type of event stimulated. •Chromosomal instability •Mini satellite instability 2
  3. 3. Genetic instability can also have a specialized role in the generation of variability in developmentally regulated processes, such as immunoglobulin (Ig) diversification. “Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders and yet it is also crucial for evolution” Nevertheless, genetic instability is usually associated with pathological disorders, and in humans it is often associated with • Premature ageing •Various types of cancer •Inherited diseases Drive evolution at the molecular level and generate genetic variation. 3
  4. 4. Chromosomal instability (CIN) • Chromosomal instability (CIN) refers to changes in chromosome structure and number that lead to chromosome gain or loss. • CIN is caused by failures in either mitotic chromosome transmission or the spindle mitotic checkpoint. Micro- and mini-satellite instability (MIN) leads to repetitive-DNA expansions and contractions and can occur by 1.Replication slippage 2.Mismatch repair (MMR) impairment 3.Homologous recombination (HR). 4
  5. 5. Reasons for genetic instability • Replication as a source of DNA breaks • Suppressors — proteins that act to prevent GIN • Fragile sites • DNA secondary structures at DNA repeats • Transcription-associated instability 5
  6. 6. Replication as a source of DNA breaks • DNA is most vulnerable during the S phase of the cell cycle. • Replisome must overcome RF stalling. • MCM4, RFA1, 2 and 3, CHK 1 and RAD53 are genes related to cancer predisposition • Classic genetic studies in E. coli and S. cerevisiae have shown that mutations in following strongly increases the levels of spontaneous chromosomal exchanges. – DNA ligase I – DNA polymerase I (α in S. cerevisiae) – DNA polymerase III (δ in S. cerevisiae) – Replication factor A – DNA thymidylate kinase or DNA adenosine methylase 6
  7. 7. Suppressors of genome instability • Suppressor is a gene or protein that acts in trans to preserve genomic integrity. • p53 is a protein that functions to block the cell cycle if the DNA is damaged. If the damage is severe this protein can cause apoptosis • p53 levels are increased in damaged cells. This allows time to repair DNA by blocking the cell cycle. • A p53 mutation is the most frequent mutation leading to cancer. An extreme case of this is Li Fraumeni syndrome. • The Ataxia telangiectasia mutated (ATM) and ATR gene could be considered as a caretaker gene. 7
  8. 8. DNA damage is caused by heat, radiation, or chemicals. p53 allows cells with repaired DNA to divide. Step 1 DNA damage is caused by heat, radiation, or chemicals. Step 1 Step 2 Damaged cells continue to divide. If other damage accumulates, the cell can turn cancerous. Step 3 p53 triggers the destruction of cells damaged beyond repair. ABNORMAL p53 NORMAL p53 abnormal p53 protein cancer cell Step 3The p53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA. Cell division stops, and p53 triggers enzymes to repair damaged region. Step 2 DNA repair enzyme p53 protein p53 protein p53 — master regulator gene 8
  9. 9. •Ataxia telangiectasia mutated (ATM) - a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. •It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX which are tumor suppressors. Germline mutations in caretaker genes can explain the presence of genomic instability in inherited cancers, the molecular basis of genomic instability in sporadic cancers remains unclear. 9
  10. 10. 10
  11. 11. Fragile sites • Fragile sites are DNA sequences that show gaps and breaks following partial inhibition of DNA synthesis. • Hotspots for translocations and other rearrangements. • There are two types of fragile sites, common and rare. • Common fragile sites account for more than 95% of all known fragile sites and are naturally present in mammalian genomes. • Rare fragile sites, also known as dynamic mutations. • Rare fragile sites are associated with genetic diseases, such as – Fragile X mental retardation syndrome – Friedrich’s ataxia – Huntington disease • These are caused by the effect of the DNA expansion at the RNA or protein level of the locus affected. 11
  12. 12. DNA secondary structures at DNA repeats • Fragile sites are usually associated with trinucleotide repeats (TNRs) of the type CGG–CCG, CAG–CTG, GAA–TTC and GCN–NGC, with specific G-rich repeats or with long AT-rich repeats. • Fragile sites are conserved in mammals and the molecular basis of their instability is inherent in their DNA structure. • Thus, instability of TNRs and AT-rich minisatellites seems to be associated with their capability to adopt unusual secondary structures, such as hairpins or DNA triplexes. 12
  13. 13. Models of double-stranded break formation at fragile sites 13
  14. 14. Transcription-associated instability • Transcription stimulates – recombination i.e. transcription associated recombination (TAR) – mutations called transcription-associated mutation (TAM) • Key to the understanding of TAR and TAM is the fact that ssDNA is chemically more unstable than dsDNA. For example, spontaneous deamination of cytosine to uracil by hydrolysis occurs 140-fold more efficiently on ssDNA than on dsDNA in vivo. • Genotoxic agents such as 4-nitroquinoline 1-oxide or methyl- methanesulphonate increase recombination efficiency more than 100-fold when a gene is transcribed. 14
  15. 15. 15 Hairpin and R Loop formation during transcription
  16. 16. Telomere shortening 16
  17. 17. •During the cell division, genomic instability is minimized by four major mechanisms High fidelity DNA replication in S phase Chromosome segregation during mitosis Error free repair of sporodiac DNA damage A coordinated cell cycle progression 17
  18. 18. 18 During the cell division cycle , 4 major mechanisms are involved in maintaining genomic stability : 1.Fidelity of DNA replication (s phase) 2.Accurate segregation of chromosomes 3.Precise repair of DNA damage 4.Cell cycle checkpoints Fidelity of DNA replication in s phase : 1.DNA polymerase 2.Telomere maintainance 3.Restart of stalled replication forks 4.Maturation of okazaki fragments Segregation of chromosomes in mitotis : 1.Centrosome duplication and chromosome 2.Spindle formation and checkpoint 3. Chromatid seperation 4. Cytokinesis Precise repair of DNA damage : 1. DNA damage pathways 2.DNA repair checkpoints Diagram showing major mechanism to maintain genomic stability during cell cycle
  19. 19. Tumor – is a condition where there is abnormal cellular growth thus forming a lesion or in most cases, a lump in some part of your body. Benign tumor – grows in confined area Malignant tumor – capable of invading surrounding tissues Cancer – degenerative disease with a cellular condition where there is uncontrolled growing mass of cells capable of invading neighboring tissues and spreading via body fluids to other parts of the body. Cancer 19
  20. 20. 20 • Benign tumors generally do not spread by invasion or metastasis • Malignant tumors are capable of spreading by invasion and metastasis Malignant versus Benign Tumors
  21. 21. 21 Cellular Basis of Cancer • Cancer is a collection of diseases characterized by abnormal and uncontrolled growth • Cancer arises from a loss of normal growth control • In normal tissues, the rates of new cell growth and old cell death are kept in balance • In cancer, this balance is disrupted • This disruption can result from 1) uncontrolled cell growth 2) loss of a cell's ability to undergo apoptosis
  22. 22. Normal cells vs. Cancer cells Normal cell proliferation Cancer cell proliferation Density-dependent inhibition Can grow on top of one another Limited number of cell divisions Immortal Telomere shortening Telomere maintenance Proliferation dependent upon extracellular signals Constant signal to divide Checkpoints activated at appropriate times Loss of checkpoint Apoptosis functional Apoptosis inhibited 22
  23. 23. Oncogene - genetic material that carries the ability to induce cancer. 23
  24. 24. Development of Cancer • Cancer develops only after a cell experiences ~6 key mutations (“hits”) – unlimited growth • turn on growth promoter genes – ignore checkpoints • turn off tumor suppressor genes (p53) – escape apoptosis • turn off suicide genes – immortality = unlimited divisions • turn on chromosome maintenance genes – promotes blood vessel growth • turn on blood vessel growth genes – overcome anchor & density dependence • turn off touch-sensor gene It’s like an out of control car! 24
  25. 25. Genomic instability is a key hallmark of malignancy •Cancer is caused by successive gene mutations that amount to confer malignant phenotype. •Genomic instability is considered a key endogenous mechanism for accumulation of mutations, and therefore, has been proposed as an engine of tumorigenesis. Connections between Genomic Instability and Cancer whether the chicken or the egg came first comes to mind when one attempts to sort out whether a molecular change is the cause or a consequence of cancer 25
  26. 26. Genomic instability might be a potential driving force in the transformation of normal stem cells into cancer cells. Genomic instability is a characteristic of almost all human cancers, but at what stage of cancer development it arises and what its molecular basis is, are questions to which we are only beginning to get answers. 26
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