DNA damage Flashcards
what is cancer
Adaptive development of of misgrowth of normal human cells
Cancer can form tumours - distant metastasis cause problems when they are not contained
T/F blood cancers can also form tumours
False
how are cancer cells different from normal cells
- Grow in the absence of signals telling them to grow and ignore the signal which tell them to stop dividing/to die
- hide from the immune system/subvert immune system into helping cancer cells stay alive
- accumulate multiple changes in their chromosomes.
- Rely on different kinds of nutrients / make energy from nutrients in a different way than most normal cells
how does cancer move around the body
Accumulates in tumours (growths) and recruits blood vessels to grow around
- burst of tumours cause metastasises and spread of cancers
why is cancer considered a heterogenous disease
- every tumour is unique, and even a single tumour will contain different populations of cells
why is cancer difficult to treat
- heterogenous disease
- ever changing cells develop survival methods faster than they are killed
- Drug treatment leads to the evolution and selection of drug resistant tumour cells – the disease becomes refractory to treatment
- Current drug discovery strategies aim to target the identified differences between normal and tumour cells – individual profiling of disease
- However, most currently-used drugs are not exclusively active against tumour cells. Thus treatment causes unpleasant and sometimes dangerous side effects
Cancer incidences increase with _. Why?
Age
- two hit hypothesis
what is the two hit hypothesis
- Loss of tumour suppressor function requires both alleles to lose function – two-hits that take time or large amounts of damage to occur in normal cells
- The older you are, the more likely to lose allele function
- Germline mutation such as BRCA (breast cancer) were one allele is dysfunctional from birth and therefore the risk of developing two dysfunction allele
= First hit has bigger impact
Why is cancer considered a ‘Disease of the Genome’
- Cancer is a family of diseases that can arise in many different tissue types
- Cancers share the common property of uncontrolled growth of tumour cells
- Cancer is caused by the accumulation of mutations in the genome arising from DNA damage
what genes are normally mutated in cancer
Oncogenes (positive regulators of cell growth)
Tumour suppressor genes (negative regulators of cell growth)
Apoptosis and lifespan-regulating genes (cell death pathways)
Mutator (caretaker) genes (DNA damage surveillance and repair)
what envirometal factors can cause cancer
Sex, Alchol, stress, immunosuppresion, Viruses, bacteria, parasites.
X-irridiation UV irridation, Anti cancer drugs, Aflatoxin/nitrosamines, Benzopyrenes
How does cigarette smoke cause cancer
Benzo[a]pyrene (BP) is metabolised in the body to BPDE (benzo[a]pyrenediol-epoxide) which forms a covalent adduct with guanine in the DNA
how has plant fungi been linked to cancer
Aflatoxin is metabolised in the liver to the oxidised form which binds covalently to guanine in the DNA
how does ionising radiation link to cancer
○ X rays cause oxidative damage to DNA
- Hydroxyl Radicals (OH.) damage nucleic acids.
- They are produced as a result of the hydrolysis of water by ionizing radiation
What is UV radiation
○ UVA = produces mainly reactive oxygen species (ROS)
(Responsible for majority of sunburns and can cause skin cancer, 320-400 nm = 95% of UV reaching the earths surface)
○ UVB = produces thymine photoproducts in the DNA
(penetrates deeper into the skin, causing ageing but contributes much less towards sunburn, 280-320 nm = Most of the UVB is absorbed by the ozone layer)
○ UVC = (most dangerous of all, but is completely blocked by the ozone layer, 290 nm = UVC is absorbed by molecular oxygen)
what is sun damage and how does it link to cancer
sun beads (more intense = cumulative risk)
- The more a sunbed is used, the greater the risk of skin cancer.
- Using a sunbed ≥ once a month can increase risk by >50%.
- 100 deaths from melanoma every year in the UK.
what is sun burn
= a clear sign that UV had damaged DNA
- Once every 2 years can triple risk of melanoma
- UV damages some cells so severely that they can not be repaired and must be destroyed. Peeling is the body’s way of getting rid of damaged cells.
- This is necessary because damaged cells are at risk of becoming cancerous.
- Although skin peels and new skin layers form, some sunburn damage may remain, increasing cancer risk
What chronic infections has been linked cancer
○ ~20% of cancers world-wide are caused by chronic infections
○ Chronic infections lead to persistent inflammation at sites of infection
Example
= Infection with helicobacter pylori (HP) increases the risk of stomach cancer in the lower part of the stomach by around 6 times. 93% of patients with gastric tumours have HP compared to 18% healthy controls
= Long term infection with hepatitis B or C virus increases the risk of developing primary liver cancer because it causes damage to the liver (cirrhosis).
= Human papilloma virus (HPV) is associated with a high risk of developing cervical cancer – in the UK, girls and boys aged 12-13 are offered the Gardasil vaccine
what are some endogenous causes for cancer
- Spontaneous DNA damage
- Growing cells are exposed to free radicals (OH.) produced during aerobic metabolism (Oxidation causes the same type of damage as ionising radiation)
- Issues with metabolism & replication errors
DNA has limited chemical stability - explain how this has been linked to cancer
○ Hydrolysis of glycosyl bonds between base/sugar leads to base loss in the DNA (e.g. Hydrolytic deamination)
= Cytosine → Uracil
○ S-adenosyl methionine (SAM) is a 1C donor in intermediary metabolism and can methylate bases in the DNA (nonenzymatic methylation)
○ DNA polymerases acting at replication forks can produce replication errors (e.g. insertions). Strand slippage causes displacement and excision of nucleotides leading to deletion
T/F Cancer treatment can cause cancer
○ One of the most severe side effects of cancer therapies is the diagnosis of second primary cancers (following treatment with e.g. Cyclophosphamide, Temozolomide, Topoisomerase I and II poisons, Radiotherapy
○ These are unrelated to the original cancers, and have been proven to arise as a result of the drugs used to treat the primary cancers
- These second primary cancers are estimated to account for one in six of all new cancer diagnoses in the UK
what phase of DNA replication can error occur which have been linked to cancer
S phase
=Polymerase copies parental template strands, inserting correct bases, If there are gaps or modified bases, the template lacks the necessary information to form the correct sequence in the nascent (new) strands
Potential errors = Insertion of wrong base, addition/deletion of short sequences, Double strand breaks
what is the consequences of errors with S phase
- Loss of chromosome segments
- Exchange of sequence (recombination) between chromosomes
- Stalling of replication fork at damaged sites (reiterated replication of sequences leading to amplification)
what genes has been linked to lung cancer, and how does this link to smoking
K-ras (oncogene) and p53 (tumour suppressor) are two of the most frequently mutated genes in smoking related lung cancer
= Benzo(a)pyrene (Potts’s soot component) is linked to these mutations:
= In the 12th codon of K-ras GGT (Gly) becomes TGT (Cys); the G12C Ras, activating mutation
= In p53, three key sites undergo G to T transversion; inactivating mutations of p53
names some types of mutation
Point mutation, Deletion, Insertion, Frame shift
What are the consequences of damage to DNA
Base substitutions = No change, Loss /change in activity of gene product, Change of amino acid: GAG (Glu) …..AAG (Lys)
Deletions and insertions = Loss of function of gene product (AGA………A)
Gene amplification = Repeated firing of replication origins, Overexpression of gene product
Chromosomal rearrangements = Loss of gene(s), Alterations in expression, Changes in function, Creation of new fusion genes
what is the occurence of mutations, how does it change in cancer
Spontaneous = 106-108 per cell doubling per gene
DNA damage can increase mutation rates 10-100 fold
what cell types are susceptible to cancer which is linked to mutations
Cells with a high proliferative capacity (haematopoietic stem cells, intestinal epithelium)
Cells exposed to environmental carcinogens (skin, lung, gut
Cancer have a _ of the mutational processes that have been operative
signature
Signature 1A & 1B are associated with age and seen in most cancers
Signature 4 is found in cancers associated with tobacco smoking and has the mutational features associated with tobacco carcinogens
Signature 7 is seen in malignant melanoma and has the known features of UV-light-induced mutations
what are the genome defence strategies
Multiple defence strategies have evolved to limit the effects of DNA damage to the integrity of the genome:
1. A wide range of interactive DNA damage repair pathways to remove different types of damage from the DNA
2. DNA damage-activated enzymes which signal cell cycle checkpoints
3. Detoxifying enzymes e.g. free radical scavengers such as superoxide dismutase
4. Programmed cell death (apoptosis) – in a multicellular organism it is better for a cell to die than survive with a lot of damage.
