Cancer Biology Flashcards
What is the difference between a tumor suppressor gene and an oncogene?
Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumour suppressor genes cause loss-of-function effects that contribute to the malignant phenotype.
How do tumors suppressor genes drive tumours?
TSGs encode proteins that prevent inappropriate cell growth and division, and stimulate cell death
Both TSG alleles must be inactivated to promote tumour development (loss of function). Inactivation of 2nd copy can be mutation, silencing by methylation or loss of heterozygosity
Usually recessive at cell level but show dominant inheritance in familial cancer syndromes (2nd “hit” is somatic)
What are the main categories of tumour suppressor genes?
- Gatekeeper Genes: Encode proteins that control the cell cycle (inhibit S phase and action of mitogen) and regulate cell proliferation e.g. p53, Rb, and APC
- Caretaker Genes: Maintain and protect the integrity of the genome. Involved in DNA repair and help to prevent the accumulation of mutations e.g. MLH1, MSH2 and RECQ helicases.
- Landscaper genes: create environments that control cell growth e.g. PTEN
What mechanisms do tumour suppressor genes use to control cell growth and division?
Control progression within cell cycle
- includes cell cycle arrest and regulator proteins.
- RB1, TP53 and CDKN2A
Inhibit proliferation
- receptors for secreted hormones, e.g. TGF-β, suppresses c-myc expression.
Maintain the integrity of genome
- DNA repair proteins e.g. MMR
Apoptosis
- Stimulate cell death in cells deviating from normal growth, e.g. p53.
What was the first tumour suppressor gene identified?
RB1
Through investigating childhood retinoblastoma
What is retinoblastoma
An aggressive childhood cancer of the eye that is usually diagnosed <5yrs.
Can be unilateral (usually sporadic) or bilateral (these are always heritable).
Incidence ~1 in 15,000 to 1 in 20,000 live births. ~15% cases familial (transmitted from an affected parent)
15% of sporadic cases carry germline mutations
What is the role of RB1?
RB has important roles in cell cycle progression, chromosome stability and regulation of apoptosis.
RB is hypophosphorylated in G1, binds activator E2F TFs, inhibits cell cycle progression.
pRB is phosphorylated by CDKs which inactivates pRB. E2Fs are released and activate transcription, this leads to cyclin E production and eventual entry into S phase.
What is Knudson’s two hit hypothesis?
Derived investigating RB
Both alleles need to be lost requiring two hits (one to each RB gene)
Hereditary retinoblastoma:
- a mutant, loss of function germline allele is inherited (most are de novo). Later, somatic mutation inactivates 2nd allele
- This leads to variable penetrance and an apparently dominant mode of inheritance (called one-hit kinetics).
Sporadic retinoblastoma - 2 somatic mutation events must occur (two-hit kinetics).
- Second mutation may be LOH, gene silencing by promoter methylation, mutation or deletion.
What is TP53?
Guardian of the genome
p53 is in the centre of a network of signalling pathways that are essential for cell growth, regulation and apoptosis - induced by genotoxic and non-genotoxic stresses e.g. oxidative stress, ribonucleotide depletion, double strand breaks, hypoxia
What is the function of TP53?
Normal cells:
- p53 levels downregulated via binding of proteins such as the E3 ubiquitin ligase, MDM2.
- MDM2 binding causes p53 migration to cytoplasm and degradation via the ubiquitin/proteasome pathway.
Stressed cells:
- p53 becomes phosphorylated and acetylated.
- No longer acts with MDM2, p53 levels rise to act as a transcription factor.
- Causes increased transcription of genes such as p21 (inhibits CDKs=cell cycle arrest; allows DNA repair before mitosis) and PUMA (controls apoptosis).
What do mutations in tp53 lead to?
Somatic mutations in TP53 in more tumour types than any other gene mutation (~50% of tumours); found in 23% of breast, 50% of cases of ovarian cancers, for example.
Li-Fraumeni syndrome, caused by p53 germline mutation. Results in a high incidence of cancer, particularly tumours of the adrenal cortex, breast, brain and osteosarcomas.
What do mutations in PTEN lead to?
PTEN is a TP53 regulated gene
Even a subtle difference in PTEN levels and activity results in cancer susceptibility and favours tumour progression.
PTEN germ-line mutations cause PTEN hamartoma tumour syndrome and Cowden syndrome.
What is the role of CDKN2A?
Encodes 2 gene products
p16INK4A : Inhibits CDK4/6, thus keeps RB dephosphorylated and bound to E2F = cell cycle arrest.
p14ARF : Destabilises MDM2 resulting in active p53 and cell cycle arrest at G1.
Inherited CDKN2A mutations mainly affect p16INK4A only e.g. familial melanoma, pancreatic cancer.
Give some miRNAs which act as tumour suppressors
let-7
- Normally expressed in differentiated tissues, but frequently lost in non-small lung cancers
- let-7 negatively regulates multiple cell cycle oncogenes, such as RAS, MYC, and HMGA26–8
- Exogenous application of let-7 to human lung cancer cells reduces proliferation
miR-34 family
- Also lost in lung cancer
- Transcription is activated by p53, expression of miR-34a promotes p53 mediated apoptosis
- Acts as a TSG, represses multiple cell cycle and cell survival genes e.g. CDK4 and BCL2
- Required for a radiation response in vitro and in vivo.
What is an oncogene?
A gene that is normally is involved with controlling cellular proliferation.
When altered/over-activated, oncogenes can help transform normal cells into tumour cells by promoting uncontrolled cell growth and/or inhibiting apoptosis.
What are the three main methods of oncogene activation?
Point mutation
Translocation
Gene amplification
How do point mutations drive oncogene activation?
Activating point mutations lead to hyper-activated protein usually produced in normal amounts
How do RAS point mutations lead to oncogene activation?
HRAS, KRAS and NRAS mediate signaling by G-protein coupled receptors. Point mutations in these genes can lead to constitutive activation of downstream GTP-signaling by blocking integral GTPase activity (which acts as a molecular switch). These mutations are often identified in metastatic colorectal cancer, as well as cancers of the lung, breast and bladder.
How does amplification lead to oncogene activation?
Multiple copies of growth factor or transcription factor receptors on structural wild type cell surface, which leads to over-production coding protein
e.g. HER2 in breast cancer and MYC in rhadomyosarcoma
How do translocations lead to oncogene activation?
Translocation to create a novel chimeric gene
- the product of an acquired balanced translocation where a fusion gene with an oncogene is create
- e.g. BCR-ABL1in CML
Translocation into transcriptionally active region
- acquired balanced translocations between oncogene and region with high transcription regulatory elements, leading to the oncogene being upregulated in expression
- e.g. IGH-MYC in burkitt lymphoma where MYC is brought under the control of IGH promoter
What are 5 classes of oncogenes?
Secreted Growth Factors
Growth Factor Receptors
Signal Transducers
Inhibitors of Apoptosis
Transcription Factors
Give an example of a secreted growth factor oncogene
Constitutive activation of a growth factor gene can contribute to malignant transformation by inducing cell proliferation.
Platelet-derived growth factor (PDGF) is released from platelets during coagulation and wound healing and can induce proliferation of various adjacent cell types.
Over-expression of PDGF-b in tumour cells triggers unregulated cell growth via the RAS/PIK3/AKT/IKK/NFKB1 pathway and is involved in angiogenesis (formation of new blood vessels from existing ones)
Give an example of a growth factor receptor oncogene
Epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), activating mutations in exons 18, 19 and 21 of the EGFR gene, which code for part of the protein’s tyrosine kinase (TK) domain, cause increased kinase activity of this receptor.
Such activating mutations confer a dependence on the mutated kinase for survival of the tumour cells.
Mutations occur around the ATP-binding pocket of the receptor protein. Mutated kinases have a lower affinity for ATP that increases their sensitivity to selective EGFR-TKIs, which compete with ATP for binding to the catalytic site.
Give an example of a signal transducer oncogene
PIK3CA acts as an oncogene by encoding a mutated, constitutively active form of the PI3K enzyme, leading to continuous activation of the PI3K/AKT/mTOR pathway, which promotes uncontrolled cell proliferation and survival. This persistent signaling supports cancer development by enhancing cell division, inhibiting apoptosis, and reprogramming cellular metabolism.
Give an example of an inhibitor of apoptosis oncogene
The BCL2 gene encodes a cytoplasmic protein that localises to the mitochondria and inhibits apoptosis.
Over-expression of BCL2 protein is involved in the initiation of almost all follicular lymphomas and some diffuse large B cell lymphomas.
In follicular lymphoma a t(14;18) translocation commonly occurs which places the BCL2 gene next to the immunoglobulin (Ig) heavy chain locus. This leads to the transcription of excessively high levels of BCL2, decreasing the propensity of these cells to undergo apoptosis.
How does is apoptosis triggered?
Two main pathways (stress response and death) lead to apoptosis:
The stress pathway (or intrinsic cell death pathway) is triggered by proteins containing the BCL2 homology 3 domain which inactivate BCL-XL and BCL2 (these normally inhibit apoptosis). This removal of suppression activates the caspases that induce apoptosis.
The death receptor pathway (or extrinsic pathway) is activated by binding of Fas ligand, TRAIL and Tumour Necrosis Factor a to receptors on the cell surface. This leads to activation of caspases and cell death.
Give an example of a transcription factors oncogene
EWSR1
Ewings sarcoma (tumours in the bones and soft tissues) occurs as a result of the translocation t(11;22)(q24;q12) which results in the translocation of the 3’ end of the Friend leukaemia integration 1 TF (Fli1) on chromosome 11 to the 5’ end of the EWS gene on chromosome 22 (80% cases).
The resulting novel chimeric oncoprotein produced, EWS/Fli1, acts as an aberrant transcription factor with strong transforming capabilities.
What are the stages of the cell cycle?
G0
Interphase
- G1
- S
- G2
Cell division
- Mitosis
What is G0 phase?
A resting phase where the cell has left the cycle and has stopped dividing. These cells are not dormant and often actively secrete proteins, may be highly mobile and can continue growing. In response to certain stimuli, these cells can re-join the cell cycle.
What is G1 phase?
Growth phase during which proteins and RNA are synthesised. Each chromosome exists as a single double stranded helix - at no point is DNA synthesised in this phase.
At the G1 checkpoint - the restriction point - the cell is committed to division and moves into the S phase
What is S phase?
DNA synthesis replicates the genetic material. Each chromosome now consists of two sister chromatids.
What is G2 phase?
Cell continues to grow. The G2 checkpoint ensures enough cytoplasmic materials necessary for mitosis and cytokinesis.
What is M phase?
The cell stops growing. Nuclear division (mitosis) followed by a cell division (cytokinesis). The Metaphase checkpoint in the middle of mitosis ensures that the cell is ready to complete cell division.
What are cell cycle checkpoints?
Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions ensuring critical evens are completed with high fidelity
What proteins regulate the cell cycle?
The cell cycle is regulated by heterodimeric protein kinases composed of:
Cyclins - these form the regulatory subunit and have no catalytic activity.
Cyclin-dependent kinases (CDKs) - proteins which are inactive in the absence of a partner cyclin. They are the catalytic subunit of an activated heterodimer which phosphorylates target proteins to coordinate entry into the next phase of the cell cycle.
CDKs are constitutively expressed whereas Cyclins are synthesised at specific stages in response to various external stimuli / molecular signals.
What are the cell cycle checkpoints and why are they needed?
Cell examines queues and decides whether to move forward. 3 main ones:
G1 checkpoint, at the G1/S transition
- G2 checkpoint, at the G2/M transition
M checkpoint, also called Spindle checkpoint, at the Metaphase/Anaphase transition
Failure to activate checkpoints allows cells to divide when there is DNA damage or when chromosomes are incorrectly placed, thus causing genome instability
What is the G1 checkpoint?
G1 checkpoint
- Main decision point; once G1 checkpoint is passed and S phase entered, the cell becomes irreversibly committed to division
- Factors: DNA integrity, molecular signals, nutrients, cell size
- Cell growth enables CDK-cyclin D formation
- Phosphorylates retinoblastoma protein
- Relieves inhibition of E2F transcription factor
- Cyclin E now expressed, binds to CDK2
- Allows G1-S phase transition
What is the G2 checkpoint?
CDK1 is activated by phosphorylation and de-phosphorylation of specific amino acid residues by Cyclin-Activating Kinase (CAK) and the wee1 protein
Enables CDK1-cyclin B formation (aka MPF)
Allows G2-M phase transition
What is the M checkpoint?
Chromosomes assemble on metaphase plate
Cell examines whether sister chromatids correctly attached to spindle microtubules
Anaphase-promoting complex (APC) activated
Degrades cyclin B = MPF disassembly
Relieves inhibition of ‘separase’ (a cysteine protease) = spindle cut
Sister chromatid separation = anaphase entry
How can the cell cycle lead to tumourigenesis?
A negative control on cell cycle progression plays an important role in preventing tumorigenesis.
The arrest of cell proliferation in many cases takes place when integrity of the genome has been compromised. Failure to arrest results in the release of cells with highly unstable genomes, which could evolve into cancer cells.
What is the function of cyclin D1?
Cyclin D1 is a growth factor-responsive cyclin that plays an important role in regulating entry into and progression through G1. Deregulated expression of cyclin D1 could increase cyclin D1/CDK4 activity and drive transit of the checkpoint even in the absence of appropriate growth factors. Cyclin D1 expression can be induced by the Ras and PI3 kinase signalling pathways.
What is the role of p53 in the cell cycle?
it stops the cell cycle at the G1 checkpoint by triggering production of CDK inhibitor (CKI) proteins. The CKI proteins bind to CDK-cyclin complexes and block their activity, buying time for DNA repair. p53’s second job is to activate DNA repair enzymes. If DNA is not fixable, p53 will play its third role: triggering programmed cell death.
In normal cells, p53 is kept at low levels by the protein murine double minute 2 (MDM2), an ubiquitin ligase. MDM2 and p53 form a negative feedback loop, in which p53 induces the expression of MDM2, which in turn promotes the degradation of p53 and quenches cellular p53 activity.
What is the role of RB1 in cell cycle?
Active, dephosphorylated pRb binds and inactivates the cellular transcription factor E2F1, function of which is required for cell cycle progression. The G1/S checkpoint seems to be the most crucial for the cell cycle; 2-4 hours before the cell enters S-phase, pRB is phosphorylated. This releases the inhibition of E2F1 and allows the cells to proceed to S phase
What is the role of CDKN2A in the cell cycle?
Exons 1α, 2 and 3 encode the CDKN2A (p16INK4A) protein.
- CDKs inactivate pRB by phosphorylation, but CDKN2A inhibits the kinases. Thus, the loss of CDKN2A function leads to the loss of RB1 function and inappropriate cell cycling.
Exon 1β is spliced on to exons 2 and 3, but the reading frame is shifted, protein ARF (p19ARF) is encoded.
- ARF mediates G1 arrest by destabilising MDM2 and therefore ARF acts to maintain the level of P53. Loss of ARF function leads to excessive levels of MDM2, excessive destruction of P53, and loss of cell cycle control.
How does inactivation of CDKN2A drive tumourigensis?
Homozygous deletion of the CDKN2A gene inactivates both the RB1 and the p53 arms of the cell cycle control, and is a very common event in the development of many tumours (e.g. mesothelioma).
How can MDM2 be targeted therapeutically?
Blocking MDM2 expression – limits its interaction with p53, therefore preventing p53 degradation and resulting in higher levels of p53 in cells.
Inhibiting MDM2-p53 binding
- p53-MDM2 interaction has been demonstrated to involve only three amino acid residues which are inserted into deep hydrophobic pockets on the surface of the MDM2 protein- small molecules being investigated
When in the cell cycle can structural abnormalities be assessed by karyotyping?
Metaphase
Give an example of a structural rearrangement of cyclin D1 (CCND1) (genes and chromosomal abnormality) and the associated disease.
IGH::CCND1 t(11;14) – Myeloma or Mantle cell lymphoma or other
What are the three main growth factor signaling pathways?
RAS/MAPK, PI3K/AKT or JAK/STAT
What are receptor tyrosine kinases?
Cell surface receptors activated by ligand binding (generally GF)
Ligand binding triggers dimerization of receptors, which activates intracellular tyrosine kinase domains.
Intracellular TK domains phosphorylate their own tyrosine residues = activation of downstream signalling.
Examples include ALK, ROS, EGFR, HER2, KIT, PDGFRA, FLT3 and TRK
What is the structure and function of EGFR?
Structure: extracellular ligand binding domain, short hydrophobic transmembrane region and intracytoplasmic TK domain
Important role in regulating various cellular functions such as proliferation, motility and differentiation
Ligand binding causes dimerization, followed by autophosphorylation and activation of downstream signalling pathways
What is the role of RAS/MAPK signaling?
Key signalling pathway that regulates a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses
RAS mutations are detected in approximately 30% of all tumours
Mutations in RAS or RAF result in constitutively activated MAPK pathway, leading to uncontrolled cell proliferation and resistance to apoptosis-inducing drugs
Outline the RAS/MAPK pathway
Activated via two pathways:
- a ligand-dependent pathway e.g. EGFR
- a ligand-independent pathway, physical stressor, such as radiation, injury,
Activation of a receptor tyrosine kinase triggers phosphorylation of RAS (KRAS, NRAS or HRAS) which is a GTPase. Phosphorylation with adaptor proteins GRB2 result in inactivate RAS-GDP turning to active RAS-GTP.
This activates RAF (BRAF, ARAF or CRAF) which phosphorylates MEK and then ERK which are imported into the nucleus and activates transcription factors for proliferation, survival, apoptosis
Why are RAS proteins difficult to target therapuetically?
Structure or RAS- lack of well-defined druggable nooks and cavities on the RAS surface
Sortorasib targeting KRAS G12C is the first approved drug- NSCLC
What is the PIK3/AKT pathway?
Highly conserved pathway involved in cell survival, growth and proliferation.
Two major functional proteins: PI3K (plasma membrane-associated lipid kinases) and AKT
Pathway alterations occur in 50% of tumors and is the primary mechanism causing cancer cells to develop radiation resistance
Outline the PIK3/AKT pathway
PI3K-alpha (PI3Kα) is a heterodimeric protein complex
Activation of a receptor tyrosine kinase (RTK) triggers PI3K-mediated phosphorylation of PIP2 to PIP3.
PIP3 activates PDK1 which in turn activates AKT
Activated AKT phosphorylates TSC2, which is a negative regulator of mTOR and leads to downstream mitogenic signalling, MYC being one of these targets
PI3K requires multiple inputs for full activation, including binding by membrane-bound RTKs and Ras
PTEN negatively regulates this process
What is JAK/STAT pathway?
JAK-STAT pathway is essential for a wide of critical cellular events such as haematopoiesis, lactation, development of immune systems and mammary glands
Major role in transferring signals from cell-membrane receptors to nucleus
50-95% patients with myeloproliferative neoplasms (MPNs) have an activating mutation in JAK2 in the malignant clone
Outline the JAK/STAT pathway
Ligand binding triggers receptor dimerization- phosphorylation of specific tyrosine residues that activates JAK tyrosine kinase domain.
Active JAKs recruit signal transducers and activators of transcriptions (STATs)
The STATs form dimers that translocate to the nucleus. The STAT dimers bind specific promoter sequences and modulate transcription of genes controlling cellular processes including proliferation, differentiation and apoptosis
What is NOTCH signalling?
Notch signalling cascade is critical for development (eg. neurogenesis, development of haemotopoietic stem cells, B-cells an T-cells), differentiation, proliferatiom and homeostasis.
4 receptors: NOTCH 1-4
Mutations in Notch1 were detected in more than 50% of T-cell acute lymphoblastic leukaemias (T-ALL).
activating NOTCH1 mutations in 8-12% of cases - primarily found in patients with the more clinically aggressive nonmutated IGV(H) subtype
Outline the NOTCH pathway
Ligand binding promotes two proteolytic cleavage events in the Notch receptor.
The first cleavage is catalysed by ADAM-family metalloproteases, whereas the second is mediated by γ-secretase, an enzyme, PEN2 and APH1.
The second cleavage releases the Notch intracellular domain (Nicd), which then translocates to the nucleus and cooperates with CSL and its coactivator Mam to promote transcription.
What is the Wnt/B-catenin?
Highly conserved pathway essential for development and one of the most commonly dysregulated associated with tumorigenesis.
The Wnt pathway is commonly divided into β-catenin dependent (canonical) and independent (non-canonical) signaling.
Loss of APC is the main driver of Wnt signaling in colorectal cancer
What is the canonical WNT signalling pathway?
Upon binding of secreted Wnt ligands to Fzd receptors and LRP co-receptors, the destruction complex is inactivated and accumulation of β-catenin which then translocates into the nucleus.
There, β-catenin forms an active complex with LEF and TCF proteins by displacing TLE/Groucho complexes and recruitment of histone modifying co-activators
In the absence of Wnt ligands, β-catenin is phosphorylated by the destruction complex which contains the scaffold protein Axin, APC and the kinases GSK3β and CK1α. β-catenin is then ubiquitinated by β-TrC and targeted for proteasomal degradation, leading to repression of target genes.
What is HH signalling?
Plays an important role in the embryonic development - mostly inactive or poorly active in the adult organism
involved in the maintenance of somatic stem cells and pluripotent cells
Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer e.g. PTCH1 and gorlin syndrome, and sporadic cancers, BCC, medulloblastomas
Outline the HH pathway
Hh signalling is activated by binding of Hedgehog ligand to Ptch1. HH-Ptch1 complex is internalised and degraded by lysosome. This relieves Smo inhibition and Smo becomes phosphorylated by PKA and CK1.
The inhibitory effect of Sufu is removed and Gli activator is formed. The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters.
What is TGF-B/SMAD pathway?
TGF-β/SMAD4 signaling pathway controls the signal transduction from cell membrane to nucleus, and is responsible for a wide range of cellular processes, including proliferation, differentiation, apoptosis, migration, as well as cancer initiation and progression
Dual role in cancer: TGF-β inhibits cell proliferation and stimulates differentiation in normal cells, thus acting as a tumor-suppressor factor. However,iIn advanced cancer TGF-β acts as an oncogene by inducing tumour progression and metastasis
Outline the TGF-B/SMAD pathway?
TGF-β binds to receptors at the cell surface, forming a bi-dimeric receptor complex and causes activation of TGF-β receptor transmembrane dual specificity kinase.
Upon ligand binding the type II receptor phosphorylates serine and threonine residues in the type I receptor, which subsequently propagates the signal through activation of Smad family of TFs.
What is NF-kB?
comprises a family of five transcription factors that functions to regulate expression of genes involved in proliferation, apoptosis, inflammation and immune response. Required at low level for normal haematopoiesis.
Constitutive NF-κB activity is found in many cancers due to inflammatory microenvironment and oncogenic variants – promotes tumour cell proliferation, suppresses apoptosis, attracts angiogenesis, induces EMT and facilitates distant metastasis.
Common in NHL
Outline the NF-kB pathwat
NF-κB can be activated by various stimuli, such as cytokines, growth factors UV and ionizing radiation, reactive oxygen species (ROS), and DNA damage and oncogenic stress from inside the cells.
Lead to the activation of a large cytoplasmic protein complex.
The activated IKK complex is responsible for the phosphorylation of IκB, marking it for degradation by the E3 ubiquitin ligase.
Following proteosomal degradation, the free NF-κB dimers can translocate from the cytoplasm to the nucleus, bind to DNA and regulate gene transcription.
How does DNA damage relate to cancer development?
DNA damage has been long recognized as a causal factor for cancer development.
Every cell experiences up to 10^5 spontaneous or induced DNA lesions per day.
When erroneous DNA repair leads to mutations or chromosomal aberrations affecting oncogenes and tumour suppressor genes, cells undergo malignant transformation resulting in cancerous growth
What are the causes of DNA damage?
Chemical carcinogens
Radiation
Oxidative stress
Replication errors
Viruses and oncogenic pathways
How do chemical carcinogens lead to DNA damage?
- They can be divided into two main categories: genotoxic and non-genotoxic.
- Genotoxic carcinogens directly interact with DNA, leading to alterations such as base modifications, cross-linking, and strand breaks.
- Non-genotoxic carcinogens induce cancer through mechanisms not directly related to DNA damage but may still lead to genomic instability and tumorigenesis.
How does radiation lead to DNA damage?
Ionizing radiation, such as X-rays, gamma rays, and certain types of ultraviolet (UV) radiation, can directly damage DNA by generating reactive oxygen species (ROS) and causing breaks in the DNA backbone.
- UV radiation primarily induces formation of cyclobutane pyrimidine dimers (CPDs), leading to mutations if not repaired properly.
