Nucleotide Excision Repair Factors

Slide 1 · Nucleotide Excision Repair Factors

UV-induced DNA damage, repair failure and cancer predisposition

Molecular pathology and clinicopathologic correlations

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how UV-induced pyrimidine dimers interfere with DNA replication.

Connect nucleotide excision repair failure to xeroderma pigmentosum and skin cancer.

Distinguish nucleotide excision repair from the other genomic stability pathways.

Use molecular injury–repair logic to interpret clinical and pathological examples.

Slide 3 · Genomic instability accelerates cancer evolution

Reduced genome protection

Mutations accumulate faster

Driver alterations acquired

Tumor progression

Schematic

Slide 4 · Mutation rates matter as well as mutation identity

Cancer requires genetic alterations that confer a selective growth or survival advantage.

Genome-protective machinery normally restrains the rate at which new variants appear.

When repair fails, additional potential driver events can accumulate more rapidly.

This accelerated state as a “mutator” phenotype.

Slide 5 · DNA injury does not necessarily become a fixed mutation

DNA-damaging exposure

Damage detected and repaired

Replication retains fidelity

Schematic

The carcinogenic risk increases when damaging lesions persist or are repaired inaccurately.

Slide 6 · P53 links DNA damage to cell fate

DNA injury

P53-dependent cell-cycle arrest

Opportunity for repair

Schematic

If the genome is irreparably damaged, p53 can instead initiate apoptosis.

Slide 7 · Loss of p53 permits damaged cells to persist

Defective p53 function

Abnormal genome survives

Error-prone rejoining / rearrangement

Schematic

P53 loss with aneuploidy and complex chromosomal alterations.

Slide 8 · Different DNA lesions recruit different safeguards

Predominant problem

Protective process

UV-induced pyrimidine dimers

Nucleotide excision repair

Incorrect base pairing during replication

Mismatch repair

Double-strand breaks and covalent cross-links

Homologous recombination pathways

DNA polymerase copying errors

Polymerase proofreading

Slide 9 · Why UV injury is the central NER example

Ultraviolet radiation can generate covalent links between adjacent pyrimidines.

The resulting abnormal DNA structure interferes with faithful replication.

The nucleotide excision repair pathway normally corrects this class of injury.

Failure is illustrated clinically by xeroderma pigmentosum.

Slide 10 · Ultraviolet wavelengths have different biological reach

Band

Wavelength

Relevance in Robbins

UVA

320–400 nm

Part of sunlight reaching the skin

UVB

280–320 nm

Major direct pyrimidine-dimer carcinogen in skin

UVC

200–280 nm

Mutagenic, but normally filtered by ozone

Slide 11 · UV-associated skin cancer risk is contextual

Intensity and pattern of UV exposure affect carcinogenic opportunity.

Pigmentation modifies risk: Melanin absorbs UV photons.

Fair skin that burns readily is less protected against sunlight.

UV exposure contributes to squamous cell carcinoma, basal cell carcinoma and melanoma.

Slide 12 · From a UV photon to a DNA lesion

UV energy absorbed by DNA

Covalent bonding of nearby pyrimidines

Local DNA distortion

Schematic

Slide 13 · A pyrimidine dimer links adjacent bases on one strand

C

G

C

G

T

A

T

A

C

G

C

G

C

G

Covalent linkage of adjacent thymines

Damage lies within a strand, not between opposite strands

Schematic

Slide 14 · The location of the dimer is mechanistically important

Covalent linking of pyrimidines on the same DNA strand.

Adjacent thymidine residues are a particularly important target.

This is not a normal Watson–Crick base pair between opposite strands.

The covalent dimer is a lesion within a strand, disrupting normal duplex geometry.

Slide 15 · A pyrimidine dimer distorts the DNA helix

Adjacent pyrimidines cross-linked

Normal helix geometry perturbed

Opposite-strand pairing impaired

Schematic

Slide 16 · Why base-pair distortion threatens replication

DNA replication uses the existing strands as templates.

Pyrimidine dimers impede correct pairing opposite the damaged segment.

The structural defect can prevent normal DNA synthesis.

Repair before successful copying helps avoid mutation fixation.

Slide 17 · DNA repair can break the mutation pathway

UV-induced dimer

Functioning excision-repair system

Lesion repaired

Schematic

Schematic abstraction; Robbins does not enumerate the individual enzymatic steps in this excerpt.

Slide 18 · The nucleotide excision repair system is multicomponent

More than 30 proteins participating in nucleotide excision repair.

Several distinct genes encode factors required for normal pathway operation.

This molecular complexity explains why inherited dysfunction is genetically heterogeneous.

The provided NER passage does not specify the full protein-by-protein reaction sequence.

Slide 19 · “Excision” captures the essential repair principle

DNA contains a bulky abnormal segment

Damage-bearing material is removed

Intact DNA structure is restored

Schematic

Conceptual mechanism, not a depiction of specific NER protein order.

Slide 20 · Repair failure differs from replication proofreading

Question

Nucleotide excision repair

Polymerase proofreading

What is corrected?

UV-induced helix-distorting damage

Misincorporated bases during copying

When is it useful?

After lesion formation

During DNA replication

Cancer example

Xeroderma pigmentosum

Polymerase-mutated colon/endometrial cancers

Slide 21 · Excessive UV exposure challenges repair capacity

More UV irradiation

More dimer lesions

NER capacity may be exceeded

Schematic

Pathway saturation during excessive exposure as a proposed mechanism.

Slide 22 · Inaccurate repair may preserve viability yet create risk

Persisting UV-induced injury

Error-prone alternative repair

New mutations in surviving cells

Schematic

This mechanism as postulated, not as a quantified certainty.

Slide 23 · UV carcinogenesis requires lesion persistence and selection

Repeated UV injury

Surviving cells accumulate mutations

Oncogenic drivers selected

Cutaneous neoplasia

Schematic

Slide 24 · A UV mutational signature provides causal evidence

Sequencing of sun-exposed melanomas reveals very large numbers of mutations.

The mutation patterns are characteristic of pyrimidine-dimer damage and error-prone repair.

This links UV exposure to molecular alterations observed in the tumor genome.

The evidence supports an etiologic role of sunlight in melanoma.

Slide 25 · Skin cancers associated with sunlight

Tumor

Robbins association with UV / NER

Cutaneous squamous cell carcinoma

UV-induced DNA injury; increased risk with NER dysfunction

Basal cell carcinoma

Frequent on sun-exposed skin; increased with NER dysfunction

Melanoma

UV-associated mutational patterns, especially sun-exposed lesions

Slide 26 · Xeroderma pigmentosum is a repair-deficiency syndrome

Inherited loss-of-function variants affecting nucleotide excision repair cause the syndrome.

The pathway fails to remove UV-induced pyrimidine dimers effectively.

Patients therefore develop an extraordinarily high risk of cutaneous malignancy.

It provides a human illustration of genome maintenance as a tumor-suppressive function.

Slide 27 · The genotype–phenotype chain in xeroderma pigmentosum

Inherited NER gene defect

Deficient clearance of UV lesions

Mutations accumulate

Marked skin cancer susceptibility

Schematic

Slide 28 · Xeroderma pigmentosum is genetically heterogeneous

Robbins explicitly refers to several nucleotide excision repair genes.

Different loss-of-function gene defects can produce the same syndrome.

The shared phenotype is explained by failure of a common repair process.

The topic excerpt does not provide a complete list of the implicated loci.

Slide 29 · Xeroderma pigmentosum: Inheritance matters

Robbins’ hereditary skin cancer table identifies autosomal recessive inheritance.

Inheritance of defective repair capacity creates constitutional susceptibility.

UV exposure supplies a repeated tissue-specific mutagenic challenge.

The interaction helps explain predominance of tumors in sun-exposed skin.

Slide 30 · XPA is one documented genetic example

XPA and other repair genes

Nucleotide excision repair pathway

Xeroderma pigmentosum phenotype

Schematic

XPA among associated genes; This is not an exhaustive molecular classification.

Slide 31 · The cancer predisposition is particularly cutaneous

Cancers arising in UV-light–exposed skin.

Squamous cell carcinoma and basal cell carcinoma are specifically highlighted.

The inherited pathway defect does not itself select a particular driver mutation.

Chronic UV mutagenesis creates repeated opportunities for oncogenic change.

Slide 32 · Squamous versus basal cell carcinoma in this setting

Squamous cell carcinoma

High risk in xeroderma pigmentosum

Can develop through UV-damaged keratinocyte precursors

TP53 defects occur early in many UV-related precursors

Basal cell carcinoma

High risk in xeroderma pigmentosum

Typically affects sun-exposed skin

A distinct molecular driver pathway often involves Hedgehog activation

Slide 33 · Inherited repair failure and sporadic UV cancer converge

Constitutional NER deficiency OR intensive UV injury

Persistence of mutagenic DNA lesions

Accumulation of tumor-promoting mutations

Schematic

Different initiating circumstances can converge on UV-driven genomic damage.

Slide 34 · TP53 changes link UV injury to squamous precursors

Actinic keratoses are precursor lesions in sun-damaged skin.

Mutations of TP53 occur frequently in actinic keratoses of lightly pigmented individuals.

Many TP53 alterations occur at pyrimidine-dimer sites.

This provides a mechanistic link between UV injury and loss of p53 protection.

Slide 35 · Actinic keratosis: An early example of UV-driven change

Chronically sun-damaged epidermis

Atypical basal keratinocytes

Clonal lesions with TP53 alterations

Schematic

Slide 36 · Microscopic actinic keratosis reflects dysregulated maturation

Basal-cell atypia (dysplasia) occurs within UV-damaged epidermis.

Hyperkeratosis and parakeratosis can be prominent.

Solar elastosis may occur in the superficial dermis.

These changes are not, by themselves, proof of invasive carcinoma.

Slide 37 · Actinic keratosis versus squamous carcinoma in situ

Actinic keratosis

Basal-layer dysplasia predominates

Hyperkeratosis and parakeratosis may accompany

Superficial epidermal maturation can persist

Squamous carcinoma in situ

Full-thickness nuclear atypia

Atypia spans the epidermal thickness

Invasion is not implied by an in-situ diagnosis

Slide 38 · A skin-cancer progression model

UV-induced pyrimidine lesions

Early TP53 dysfunction / atypia

Additional driver changes

Squamous cell carcinoma

Schematic

Conceptual sequence; Not every actinic keratosis progresses to carcinoma.

Slide 39 · Squamous carcinogenesis usually requires multiple hits

Cutaneous squamous cell carcinoma involves more than a single mutation.

Additional increases in RAS signaling and decreases in NOTCH signaling.

Loss of p53 protection and accumulating mutations can cooperate.

No single molecular change explains every sporadic or inherited case.

Slide 40 · Basal cell carcinoma illustrates pathway diversity

Basal cell carcinoma is associated with activating changes in Hedgehog signaling.

It commonly arises on sun-exposed skin in lightly pigmented adults.

The risk is elevated in DNA-repair disorders including xeroderma pigmentosum.

UV injury and specific oncogenic pathway selection are related but distinct concepts.

Slide 41 · Genetic susceptibility is not the same as an acquired driver

Feature

Constitutional NER defect

Tumor-associated driver

Where present?

Inherited predisposition in the individual

Acquired in the evolving tumor clone

Main effect

High background vulnerability to DNA injury

Confers a growth/survival advantage

Representative example

Xeroderma pigmentosum repair defect

TP53 defect or Hedgehog pathway activation

Slide 42 · Clinical application: Multiple UV-site skin tumors

TEACHING VIGNETTE · HYPOTHETICAL

A patient develops numerous cutaneous squamous and basal cell carcinomas at UV-exposed sites. Family history suggests a hereditary disorder.

Question

Which genome-maintenance pathway should be considered?

Slide 43 · Clinical interpretation: Why this history is informative

The combination of sunlight-exposed tumors and inherited susceptibility points to failure of UV-lesion removal.

An NER defect is a mechanism-based explanation, not a histologic diagnosis from one tumor alone.

Squamous and basal cell carcinoma remain distinct tumor types.

Identification of a hereditary syndrome and characterization of a lesion are separate tasks.

Slide 44 · Mismatch repair guards against copying errors

Mismatch repair removes incorrectly paired bases during replication.

A G–T mismatch instead of an A–T pair.

Failure allows errors to accumulate across the genome.

It protects a different class of DNA defect from nucleotide excision repair.

Slide 45 · Microsatellite instability reveals mismatch repair failure

Short repeated DNA sequences

Mismatch repair deficiency

Repeat lengths gain or lose units

Schematic

Slide 46 · Lynch syndrome illustrates inherited mismatch repair failure

Robbins also uses the name hereditary nonpolyposis colorectal cancer (HNPCC).

The syndrome is autosomal dominant at the family level.

MSH2 and MLH1 are commonly affected mismatch repair genes.

Tumors often occur in the proximal colon.

Slide 47 · A two-hit sequence explains inherited Lynch susceptibility

One defective germline MMR allele

Somatic loss of the remaining normal allele

Mismatch repair deficient cell lineage

Schematic

Slide 48 · Sporadic microsatellite instability has a different route

Microsatellite instability is not restricted to inherited Lynch syndrome.

Sporadic colorectal carcinomas with mismatch repair deficiency.

Epigenetic silencing of MLH1 is a typical mechanism in sporadic tumors.

Identical instability phenotypes can arise from distinct inherited/acquired mechanisms.

Slide 49 · NER and mismatch repair should not be conflated

Characteristic

NER deficiency

MMR deficiency

Predominant damaged substrate

UV-related pyrimidine dimers

Replication base mismatches / repeat errors

Recognized inherited setting

Xeroderma pigmentosum

Lynch syndrome

Cancer emphasis

Cutaneous SCC/BCC

Colorectal and other Lynch-associated cancers

Molecular readout in Robbins

Failure to repair UV dimers

Microsatellite instability

Slide 50 · Homologous recombination responds to severe DNA injury

Double-stranded breaks and covalent cross-links in this repair context.

Defects in homologous recombination factors predispose to malignancy.

These damage classes differ from the UV-associated pyrimidine dimers central to NER.

Pathway comparisons should be based on substrate rather than the presence of cancer alone.

Slide 51 · Homologous recombination–associated syndromes

Condition

Affected safeguard

Salient consequences

Bloom syndrome

Helicase involved in homologous recombination

Developmental anomalies; broad cancer susceptibility

Ataxia-telangiectasia

ATM damage-response kinase

Ataxia, immune deficiency, radiation sensitivity, cancers

Fanconi anemia

DNA cross-link response pathway

Developmental anomalies, marrow failure, leukemia

Inherited BRCA1/2 defects

Homologous recombination repair

Hereditary breast/ovarian and other cancers

Slide 52 · ATM loss explains a different sensitivity pattern

ATM acts in signaling responses to double-strand DNA damage.

Ataxia-telangiectasia includes cerebellar neurodegeneration and immunodeficiency.

Patients are highly sensitive to ionizing radiation.

Leukemia and lymphoma are important cancer associations.

Slide 53 · Fanconi anemia connects cross-link repair and marrow failure

Multiple Fanconi-associated proteins function in repair of DNA cross-links.

Developmental abnormalities and hypersensitivity to cross-linking agents occur.

Bone marrow failure and leukemic transformation are major consequences.

This syndrome should not be equated with UV-specific NER deficiency.

Slide 54 · BRCA proteins help maintain chromosome integrity

BRCA1 and BRCA2 participate in homologous recombination DNA repair.

Inherited variants are associated with familial breast and other cancer risks.

Failure shifts the repair balance toward more error-prone pathways.

Chromosomal rearrangements and aneuploidy can follow.

Slide 55 · Proofreading errors are another source of the mutator phenotype

Defective DNA polymerase proofreading

Uncorrected base substitutions

High tumor mutation burden

Schematic

Slide 56 · Polymerase proofreading defects have tumor-level effects

These variants in subsets of endometrial and colorectal carcinoma.

A loss of proofreading function increases point substitutions.

Extremely high mutation burdens can generate many neoantigens.

The text links such tumors to generally strong checkpoint inhibitor responses.

Slide 57 · Lymphocytes deliberately rearrange DNA

RAG1 / RAG2 recombination activity

Antigen-receptor gene assembly

Functional B- and T-cell repertoires

Schematic

Slide 58 · AID introduces additional purposeful B-cell genome changes

Activation-induced cytosine deaminase (AID) is expressed in activated mature B cells.

It is required for class-switch recombination and somatic hypermutation.

These physiological processes are intrinsically error-prone.

Errors can produce chromosomal changes associated with lymphoid neoplasms.

Slide 59 · Choose the relevant instability mechanism

Finding

Most directly implicated pathway

Sunlight / pyrimidine-dimer damage

Nucleotide excision repair

Unstable length of short DNA repeats

Mismatch repair

Sensitivity to double-strand break injury

Homologous recombination / damage response

Excess point mutations from replicative copying

DNA polymerase proofreading

Antigen-receptor translocations in lymphoid tumors

Programmed recombination / mutagenesis

Slide 60 · Mechanism-based question: DNA lesion classification

TEACHING VIGNETTE · HYPOTHETICAL

Two neoplasms show genomic instability. One follows intense UV exposure; The other has altered lengths of short nucleotide repeats.

Question

Which pathway is most relevant in each?

Slide 61 · Mechanism-based question: Interpreting a skin precursor

TEACHING VIGNETTE · HYPOTHETICAL

An actinic keratosis contains atypical basal keratinocytes, and sequencing identifies TP53 alteration at a UV-dimer-associated site.

Question

What does the molecular result suggest?

Slide 62 · Integrated conclusions

UVB-induced pyrimidine dimers distort DNA and threaten faithful replication.

Nucleotide excision repair is a multigene barrier against these lesions.

Xeroderma pigmentosum demonstrates the cancer risk of inherited NER failure.

Mutational damage, cell-cycle protection and repair fidelity jointly shape tumor evolution.

Other repair defects produce distinctive lesion types and cancer syndromes.

Slide 63 · References and scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 7: Neoplasia — Genomic Instability (pp. 280–282) and Ultraviolet Rays (p. 289).

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 25: The Skin — Actinic Keratosis, Squamous Cell Carcinoma and Basal Cell Carcinoma (pp. 1040–1041).

Chapter 7 also discusses DNA mismatch repair, homologous recombination, polymerase proofreading and regulated genomic instability in lymphoid cells.