XP Progression

Exposure to UV Light or other carcinogens

Proteins recognize damage either through Thymine dimers occur in DNA

blockage of RNA polII global genomic proteins that recognize helical distortions

RNA polII recruits enzymes for excision repair.

Problems with recognition and/or mutations in repair enzymes cause oncogene and tumor suppressor damage. Proliferation of damaged genes causes the XP which predisposes patients to other cancers.

Excision Repair Mechanism

Transcription Coupled Recognition (more efficient) Global Genomic Recognition (less efficient)

Recognition

DNA Strand Separation

TFIIH is made up of two subunits: XPB and XPD

Incision
XPG creates the 3' incision XPF-ERCCI creates the 5' incision

Excision

DNA Repair Synthesis

Sealed by DNA Ligase 1

Dermatopathology

Melanocytic Nevi uniformly pigmented mole small (<6mm) with welldefined and rounded borders morphological progression : Normal Junctional Compound Dermal Mutations cause activation of NRAS & BRAF which leads to p16/INK4a accumulation p16 accumlulation is a protective response which inhibits CDKs 4 and 6 leading to permanent growth arrest

Dysplastic Nevi Lager (> 5mm) with sligtly raised irregular borders. Occurs on both sunexposed and protected body surfaces Can develop in melanoma through step-wise aquisiton or epigenetic changes. Dysplastic Nevi Syndrome: autosomal dominant leads to mutations in NRAS and BRAF

Melanoma >10 mm; ABC signs radial and vertical growth phases (correlates with probability of metasis) Breslow thickness describes tumor depth Tumor cells enlarged Nuclear enlarged w/ irregular contours clumped chromatin at the periphery eosinophilic RB mutations are common in familial and sporadic cases RAS, BRAF, p16/INK4a, p14/ARF, and PI3/AKT mutations can all be implicated.