2.8.

16 (HW#9)

BMS 525, Spring

Spencer Thomas

Summary: DiGiovanna and Kraemer, Shining a Light on Xerderma

Pigmentosum
Xeroderma Pigmentosum (XP) is the result of defects in the canonical
DNA damage repair (DDR) nucleotide excision repair (NER) pathway,
employed to recognize and excise bulky DNA adducts, primarily a result of
ultraviolet (UV) sun damage. First, described in the 1970s as a peculiar
disorder of sun sensitivity, it has now been established that the clinical
phenotypes of XPs, is the result of defects in one or more of the seven XP
proteins (XPA, XPB, XPD, XPE, XPC, XPF) required for NER; clinically named
by the XP protein defect. Additionally, the XP variant (XP-V) clinical disorder
is the result of defects in a low-fidelity DNA repair polymerase, Pol ,
employed to bypass UV-induced DNA damage. Two, clinically similar, NER
disorders, including Cockayne syndrome (CS) and Trichthiodystrophy (TTD)
have further established how defects in NER can lead to heterogenic
manifestations including developmental disorders, photosensitivity, and
progressive neurological deterioration (ND) .
The majority of our knowledge of XP and NER has been through
epidemiological studies and correlation between XP patients increased
susceptibility of cancer; where our understanding of XP pathophysiology is
arguably paralleled by what XP has taught us in respect to UV sun damage
and skin cancer. Initial studies of XP patients not only lead to the
mutagenicity of sun exposure and pre-mutagenic UV-induced DNA lesions, it
further established differential effects of acute and chronic sun exposure,
eventually establishing the link between sun exposure, DNA damage, and
skin malignancies. Initial observation that simply covered skin areas greatly
reduced the incidence of skin cancers in XP patients, lead to the
establishment of chronic sun exposure in melanomas. Moreover, in chronic
sun exposed skin damage, the characteristic wrinkling, sagging, and other
structural defects revealed that the sun radiation can be delineated into UV-A
and UV-B, which selectively damages epidermal, superficial, DNA or
penetrating further into the dermis, disrupting the connective tissue
collagenous peptide architecture, respectively. Collectively, the XP
epidemiological studies have revealed not a framework of melanoma and
sun damage, but the predisposing factors that can be utilized to prevent skin
malignances.
Comparison of XP cohorts has established not only the molecular
mechanisms of NER its link with UV sensitivity, but also ND, and
developmental defects associated with phenotypical characterized clinical
syndromes including XP, CS, and TTD. Although, XP, CS, and TTD, retain
similar characteristics, there phenotypical delineation is a result of specific
pathway defects in NER. Whereas all three syndromes exhibit
photosensitivity, only XP phenotypes exhibit a profound increased cancer
incidence. Comparison of TTD and XP phenotypes revealed that mutations in
XP-B or XP-D, employed by TFIIH in the local melting required for ssDNA
excision, can manifest as developmental defects, yet their extremely early

onset in TTD are much less substantial in CS, and relatively absent in XP.
Likewise, the progressive ND nature observed in XP and CS is absent in TTD,
elucidating that the recognition XP proteins in GG-NER (XP-C, XP-E) do not
have directly cause NDs, yet CS patients exhibiting mutant TC-NER
recognition (CSB) did. The importance of the various NER diseases and their
clinical phenotypes have greatly helped to resolve supplementary roles of
NER proteins, potentially independent of UV-induced DNA damage.
Finally,
XP
patients
are
ideal
for
chemopreventative
and
chemotherapeutic advancement. As, cancer is a phenotype associated with
immortality, high proliferation, and transcriptional activity, XP patients and
models are perfectly suited for preventing off-site toxicity of
chemotherapeutics. Epitomized by the 1st chemopreventative drug being
discovered in an XP cohort trial, the ability to manipulate complementary
repair pathways concomitant to targeting defects in active vs. inactive
chromatin is advantageous for not only understanding mutagenesis, but
linking genetic phenotypes to genotypical etiologies. The specificity of UVdamage and mutational signature of CCTT also implicates XP as model
system for utilizing mutational molecular signatures in prevention, diagnosis,
and prognostic measures in cancer. Ultimately, as our understanding of the
DNA repair and XP evolves, so will our ability to holistically apply
preventative and pharmacogenomics targeted at malignancies and DNA
repair defects.