After DNA damage, there are multiple
components involved in the nucleotide excision repair (NER) pathway, including
Xeroderma pigmentosum (XP) A-G and V.
The XPA and XPC gene products have been
identified and implicated in (one of) the first steps of NER, i.e. the
recognition of lesions in the DNA. The XPA protein binds to replication protein
A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for
NER. The XPA protein has been shown to bind to ERCC1 and TFIIH. It is possible
that the complex XPA/RPA may tell to the repair machinery which strand
contained the damage and therefore should be eliminated. The XPC protein bonds
to HR23B. This XPC-HR23B complex has been implicated in DNA damage recognition,
especially the cyclobutane pyrimidine dimers induced by UV-light.
It is very likely that the XPC-HR23B
complex is the principal damage recognition complex i.e. essential for the
recognition of DNA lesions in the genome. Binding of XPC-HR23B to a DNA lesion
causes local unwinding, so that the XPA protein can bind and the whole repair
machinery can be loaded onto the damaged site. The XPC-HR23B complex is only
required for global genome repair. In case of transcription coupled repair when
an RNA polymerase is stalled at a lesion, the DNA is unwound by the
transcription complex and XPA can bind independently of XPC-HR23B complex.
ERCC3/XPB gene product has a 3'-5'
ATP-dependent helicase activity involved in NER and initiation of basal
transcription. It is a subunit of the basal transcription factor TFIIH
ERCC2/XPD gene product has a 5'-3'
ATP-dependent helicase activity involved in NER. It is a subunit of the basal
transcription factor TFIIH
TFIIH fulfills a dual role in
transcription initiation and NER and the role of TFIIH in NER might closely
mimic its role in the transcription initiation process. In transcription
initiation TFIIH is thought to be involved in unwinding of the promoter site to
allowing promoter clearance. In the NER process TFIIH causes unwinding of the
lesion-containing region that has been localized by XPC-HR23B and XPA-RPA,
enabling the accumulation of NER proteins around the damaged site.
DDB2/XPE encodes a protein that is
necessary for the repair of ultraviolet light-damaged DNA. This protein is the
smaller subunit of a heterodimeric protein complex DDB1/DDB2 that participates
in nucleotide excision repair, and this complex mediates the ubiquitylation of
histones H3 and H4, which facilitates the cellular response to DNA damage. This
subunit appears to be required for DNA binding.
XPF encodes a protein that forms a complex
with ERCC1 (XPH, very rarely mutated) and is involved in the 5' incision made
XPG encodes a protein that is responsible
for the 3' incision made during NER.
At the site of a lesion NER proteins
create a DNA bubble structure over a length of approximately 25 nucleotides and
the XPG protein incises the damaged DNA strand 0-2 nucleotides 3' to the
ssDNA-dsDNA junction. In most studies the 3'-incision made by the XPG protein
appeared to be performed prior to and independently of the 5'-incision by
XPF-ERCC1. The XPG protein is required non-enzymatically for subsequent
5'-incision by the XPF/ERCC1 heterodimer during the NER process.
POLH encodes a DNA
polymerase specifically involved in DNA repair. It plays an important role in
translesion synthesis, where the normal high fidelity DNA polymerases cannot
proceed and DNA synthesis stalls. It has an important function in the repair of
UV-induced pyrimidine dimers.
XPA, ERCC3 (XPB), XPC,
ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG) and POLH (XPV) are involved
in the development of xeroderma pigmentosum (XP). XP
patients are characterized by a progressive degeneration of sun-exposed areas
of the skin and eyes. Some patients also manifest with progressive neurologic
degeneration. Individuals with XP who are younger than age 20 years have a
greater than 1000-fold increased risk of cancer at UV-exposed sites including
the skin and eyes. The median age of onset of non-melanoma skin cancer is
before age ten years. Among the eight alleles which may play a role in manifestations
of XP, seven are involved in processes of nucleic excision repair (NER): XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4
(XPF), ERCC5 (XPG); an additional class of patients referred to as XP variants
(XPV) result from deficiencies in POLH, a gene involved in semi-conservative
replication of previously damaged sites in DNA.
About 50% of XP are associated to
mutations in XPA or XPC (see below). Compared to XPB, XPD is altered in about
15% of XP. This is probably because, contrarily to the XPB helicase, the
helicase activity of XPD is indispensable for NER but not for transcription
initiation. So, there is much more XPD patients.
Somatic mutations of XP genes are rarely
Three disorders, not directly linked to
cancer, may be genetically related to XP:
Trichothiodystrophy (TTD): characterized
by a variable phenotype that include photosensitivity, ichtyosis, brittle hair,
intellectual impairment, short stature, microcephaly, protruding ears,
micrognathia. TTD is linked to mutations in the ERCC2/XPD, ERCC3/XPB and GTF2H5
(or TTDA, which encodes a subunit of TFIIH).
Cockayne Syndrome (CS) : characterized by
slow growth, cachectic dwarfism, thin dry hair, disproportionately long limbs
with large hands and feet, sensorineural hearing loss. CS patients have the
appearance of premature aging. CS has two types, A and B, linked to mutations
in ERCC6 (CSB) and ERCC8 (CSA), respectively. Cockayne Syndrome may also
accompany XP caused by genetic alterations in ERCC2/XPD),
Cerebrooculofacioskeletal Syndrome (COFS):
characterized by progressive neurologic disorder, microcephaly, prominent
noses, lare ears, growth failure. Ocular finding of microcornea, cataracts, and
optic atrophy are present along with joint contractures. The four types of
COFS, 1, 2, 3 and 4 are linked to mutations in ERCC6 (CSB), ERCC2 (XPD), ERCC5
(XPG), ERCC1, respectively.
Xeroderma Pigmentosum. Kraemer KH,
DiGiovanna JJ. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors.
SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2003 Jun 20 [updated 2011 Aug 04].