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Molecular Biology and Genetics |
Istituto di Genetica Biochimica ed Evoluzionistica CNR, 27100 Pavia, Italy [F. C., D. P., T. N., M. S.], and MRC Cell Mutation Unit, Sussex University, Falmer, Brighton BN1 9RR, United Kingdom [B. C. B., A. B., A. R. L.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Complementation tests by cell fusion have provided evidence for the existence of at least seven NER-deficient complementation groups: XP-A to XP-G. XP group C is one of the more common forms (3) . The patients from this group usually show only skin disorders and no neurological abnormalities. Cultured fibroblasts from XP-C patients exhibit very limited UV-induced DNA repair synthesis levels, ranging between 10 and 20% of normal, and are specifically defective in GGR. They are, however, capable of removing damage from the transcribed strand of active genes at normal rates (4, 5, 6) .
Phenotypic correction of XP-C cells by cDNA transfection resulted in the cloning of a partial but fully active XPC cDNA (7) . The full-length cDNA, isolated by Masutani et al. (8) , is 3558 nts long and the encoded 940-amino-acid product shows limited homology with the Rad4 protein of Saccharomyces cerevisiae. The human XPC gene spans about 24 kb, the transcribed sequence being divided into 15 exons (9) .
Masutani et al. (8) showed that the XPC gene encodes a Mr 125,000 protein that is present in a tight complex with the Mr 58,000 protein encoded by hHR23B, one of the two human homologues of the yeast RAD23 gene. Almost all of the XPC molecules appear to be complexed in vivo with hHR23B. Recent studies have shown that XPC-hHR23B binds to a variety of NER lesions and carries out the first step in NER (damage recognition) in transcriptionally inactive DNA (10 , 11) .
Characterization of the molecular defects in XP-C patients may provide a tool to define further the biological role of the XPC protein, as well as the sites relevant for its activity. Thus far, six XP-C cell lines have been characterized at the cDNA level, and eight mutations including point mutations, deletions and insertions have been described (12 , 13) .
In this report, we describe the clinical features and the cellular phenotype of 12 XP-C patients (8 from Italy, 1 from the United Kingdom, and 3 of Middle Eastern origin), as well as the mutations detected in the genomic and coding sequence of the XPC gene. For the Italian patients, the molecular analysis was extended to the parents to determine the allele inheritance and the linkage relationship of mutations. We have also investigated the level of expression of the XPC transcript by Northern analysis and the occurrence of the XPC protein by Western analysis.
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MATERIALS AND METHODS |
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. In common with most XP-C individuals described in the literature, none
of the analyzed cases showed neurological abnormalities.
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Lymphoblastoid cell lines were established by EBV transformation of peripheral blood lymphocytes from a normal donor (352/96), XP26PV, and the parents of the latter. These cell lines were cultured in RPMI 1640 (Sigma, St. Louis, MO) supplemented with 10% FCS in a 3% CO2 atmosphere.
DNA-Repair Investigations.
The response to UV irradiation was analyzed by measuring UDS, cell
survival in proliferating and nonproliferating cultures, and recovery
of RNA synthesis after exposure to UV light. The
definition of the genetic defect responsible for the UV
hypersensitivity was carried out by classical complementation assays.
Procedures for cell survival, UDS, recovery of RNA synthesis, and
genetic analysis are routinely used in our laboratory and have all been
described previously (17
, 18)
.
Western Blot Analysis.
Cells (2–5 x 106) were sonicated
on ice for 60 s in sample buffer [62.5 mM Tris-HCl
(pH6.8), 4 M urea, 10% glycerol, 2% SDS, 5%
ß-mercaptoethanol, and 0.003% bromophenol blue] and incubated at
65°C for 15 min before loading, as described by Shah et
al. (19)
. Protein samples were electrophoresed on 6%
polyacrylamide-SDS gels and transferred onto Hybond-C membrane
(Amersham, Little Chalfont, United Kingdom) at 120V for 1 h in
ice-cold transfer buffer (25 mM Tris, 192
mM glycine, and 20% methanol). The membranes
were incubated in two blocking buffers successively: for 1 h in
1% casein in PBS and for another hour in 5% skim milk in 50
mM Tris-HCl (pH7.5), 50 mM
NaCl, and 0.15% Tween 20. The blots were probed in a fresh solution of
the second blocking buffer with the first antibody (anti-XPC directed
against the last 19 amino acids of the XPC protein or the antibody
against the Mr 62,000 subunit of TFIIH
as loading control), and then with the second antibody (antirabbit
F(ab')2 or antimouse, respectively) conjugated
with horseradish peroxidase. Detection was carried out with the
enhanced chemiluminescence system (Pierce, Rockford, IL) and Hyperfilm
MP (Amersham).
Northern Blot Analysis.
RNA was extracted by a cesium chloride-gradient centrifugation
procedure from samples of 2 x 107
fibroblasts or 1 x 108
lymphoblastoid cells resuspended in 1 ml of guanidinium thiocyanate
buffer [4 M guanidinium thiocyanate and 3 M
sodium acetate (pH 6)].
Total RNA (5 µg) was electrophoresed on 1.2% agarose formaldehyde gel, stained with ethidium bromide, and blotted onto Hybond-N membrane (Amersham). Hybridization was carried out by overnight incubation with an XPC probe corresponding to cDNA nts 286-1413. The probe was obtained by PCR amplification and was radiolabeled using the megaprime DNA labeling system (Amersham). The signals were normalized against the ethidium bromide-stained signals of 28S rRNA.
Sequence Analysis of the XPC Gene.
RNA was extracted from approximately 2 x 106 fibroblasts or 2 x 107 lymphoblastoid cells using lysis with
guanidium isothiocyanate followed by phenol extraction and isopropanol
precipitation. cDNA synthesis was carried out using oligo d(T) primers,
2 µg RNA, and Mu-MLV reverse transcriptase (Life Technologies,
Inc.) in a total volume of 40 µl. After incubation for 1 h at
37°C, the mixture was diluted to 50 µl. Ten µl of the cDNA
synthesis reaction was used for PCR amplification (Amplitaq,
Perkin-Elmer, Norwalk, CT) in the buffer supplied by the manufacturer.
The whole XPC coding region was amplified in four
overlapping fragments (Table 2)
. Amplification was performed under the conditions described by Li
et al. (12)
, except for the primers F1 and F2,
which were used with the following parameters: 35 cycles at 94°C for
1 min, 60°C for 1.5 min, and 72°C for 2.5 min.
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. Fragments
less than 5 kb in length were amplified using AmpliTaq Gold
(Perkin-Elmer) and the following conditions: 1 cycle at 95°C for 12
min and 35 cycles at 95°C for 1 min and at 63°C for 10 min. The
other fragments were amplified with XL-PCR (Perkin-Elmer) in the buffer
supplied by the manufacturer. PCR conditions were 1 cycle at 94°C for
4 min and 35 cycles at 94°C for 1 min and at 68°C for 10 min. PCR
products were purified by agarose gel electrophoresis and manually
sequenced using a Thermo Sequenase radiolabeled terminator cycle
sequencing kit (Amersham). |
RESULTS |
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and classified by genetic analysis into the
XP-C group. As shown in Fig. 1
, the eight Italian patients showed similar alterations in the cellular
response to UV irradiation: drastically reduced UV-induced DNA repair
synthesis levels (with UDS levels ranging between 10 and 20% of
normal); substantial sensitivity to the killing effects of UV light in
proliferating cultures, but normal recovery of RNA synthesis at late
times after irradiation; and survival levels in nonproliferating
cultures that were significantly affected only at high UV doses.
Similar alterations have been described in the patients XP4RO, XP4BR,
XP14BR, and XP6BR (see references in Table 1
). This pattern of response
to UV light is typically present in XP cells belonging to group C, and
it reflects a specific defect in GGR. Normal TCR in XP-C cells results
in normal rates of recovery of RNA synthesis. In nondividing cells, the
ability to carry out GGR is of relatively minor importance because only
the actively transcribed regions of DNA are used, and nondividing XP-C
cells consequently have close-to-normal survival levels
(4)
.
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and data not shown), which indicated that the XPC protein in these
patients either was not present or was lacking the COOH-terminal region
that was used to raise the antibodies.
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. Eighteen mutations were detected in the open reading frame of the
XPC gene, 13 of which are relevant for the pathological
phenotype, the other 5 being polymorphisms. However, when we analyzed
the XPC cDNA from the parents using standard amplification
conditions, we were unable to detect the mutations found in the
patients in any of the cases except the father of XP13PV. This
suggested that, with this one exception, the expression of the mutant
RNA was much lower in heterozygotes than that of the normal RNA.
Therefore, in the eight Italian patients, the genomic DNA regions
containing the mutations were sequenced, and the pattern of inheritance
of the alleles was established by analyzing the relevant genomic DNA
regions of the parents.
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, the most common inactivating changes are
frameshift mutations resulting from the insertion or
deletion of one or two bases. The loss of the C residue at position 128
was detected in both alleles of patients XP12PV and XP18PV (Fig. 3B)
, and in the maternal allele of patient XP19PV—the
paternal allele carrying an AA deletion at position 1103–1104 (Fig. 3D)
. An insertion of two A residues at position 321 was
observed in both of the alleles of XP5PV (Fig. 3A)
and in
the maternal allele of XP13PV (Fig. 3C)
. Three patients were
homozygous for other frameshift mutations: insertion of a single T
residue at position 671 (XP4BR), deletion of the dinucleotide TG at
position 1643–1644 (XP26PV), and deletion of C2257 (XP9PV; Fig. 3A
). Three of the four deletions detected (namely, -C128,
-TG1643–1644, and -C2257) and the AA321 insertion occur in runs of
identical bases and are likely to result from replication slippage.
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A G2069C transversion was found in the paternal allele of XP13PV (Fig. 3C)
; this missense mutation causes the
change of amino acid 690 from Trp to Ser. Trp-690 is conserved in five
homologues (human, mouse, Drosophila melanogaster, and the
yeasts S. cerevisiae and Schizosaccharomyces
pombe), and it is located in a sequence of five amino acids that
are predicted to be in an 
-helical conformation by the PHD
secondary structure prediction protocol (20, 21, 22)
. The
alteration of Trp to Ser is predicted to destroy this -helical
conformation, so that this amino acid substitution probably induces
some change in the secondary structure of the XPC protein. The presence
of a missense mutation in this patient is consistent with the presence
of detectable XPC protein in the Western blots (Fig. 2)
.
A large deletion of 184 nts, from position 2421 to 2604, was
found in one allele of XP6BR cDNA. This deletion comprises exons 13 and
14 (9)
and could arise either as a splicing abnormality or
as a genuine deletion in genomic DNA with the deletion break points in
introns 12 and 14. The latter is supported by Southern analysis using a
3' XPC cDNA probe spanning nts 2400–3000, which showed—in
addition to the bands seen in normal cells—an extra band after the
digestion of the genomic DNA with EcoRI or BamHI
(Fig. 4)
. Because of a very low level of expression of the second allele in
XP6BR, the inactivating mutation present on this allele was not
identified.
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This mutation reduces the efficiency of the splice acceptor
site of intron 11 by interrupting the polypyrimidine tract. These two
mutations are 13 bp apart in the genomic DNA and could conceivably have
arisen from a single event. The net result is the generation of two
differentially spliced products, one of normal size containing the
C2257 deletion and the other lacking the whole of exon 12.
In the XPC coding sequences of patients XP10PV and XP26PV,
both of which contain mutations toward the 3' end of exon 8, we
observed a deletion of nts 1627–1872, corresponding to the last 246
nts of exon 8. Low levels of cDNAs with this deletion could also be
detected in the parents of both patients (Fig. 5)
. Amplification and sequencing of the regions around the mutations and
around the splice donor site of intron 8 in the genomic DNA of these
patients and their parents did not show the presence of any mutation
other than the C1735T transition in XP10PV and the TG1643–1644
deletion in XP26PV. The splice donor site of the alternative splice
event is located in the 3' third of exon 8. This exon is unusually long
(882 bp in length), which could make it unstable. The new splice site
scores 83 using the system of Shapiro and Senapathy (23)
,
well above the minimum necessary to form a splice donor site. The point
mutation in XP10PV and the two-base deletion in XP26PV are both
located toward the 3' end of exon 8 (nt 991-1872) and could induce some
change in the secondary structure of the mRNA, so that the cryptic
splice site at position 1627 is used instead of the normal one at the
beginning of intron 8. Because the two patients are homozygous, the
presence of two different splice products indicates that both normal
and cryptic splice donor sites are used.
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. These mutations are
likely to be polymorphisms because several phenotypically normal
subjects who belonged either to the general population or to families
with XP-affected members were homozygous for these changes.
Furthermore, we observed two silent mutations—C303T (Asp-101) and
G2061A (Arg-687)—and two G to C transversions located in the 5' and 3'
untranslated regions at position -27 and 2919, respectively. Expression of XPC transcripts in the Italian patients and their parents were examined by Northern blot analysis (data not shown). Compared with cells from normal donors, no significant differences were observed in the XP-C parents or in patient XP13PV. In the other patients, the levels of XPC transcript were slightly reduced with values ranging between 60 and 80% of normal.
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DISCUSSION |
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. The mutations are distributed across the gene, with no indication of
any hotspots or founder effects. Excluding the five cases analyzed only
at the cDNA level (12)
, 10 of the 13 remaining patients
are homozygotes for the mutated XPC alleles, which suggests
that they were all born from consanguineous marriages although
consanguinity has been reported in the family histories of only XP9PV
and XP18PV. The same inactivating mutations were found in XP12PV,
XP18PV, and XP19PV (the loss of the C residue at position 128); in
XP13PV and XP5PV (the insertion of two A residues at position 321); and
in XP4PA and XP26PV (deletion of the dinucleotide TG at position
1643–1644). However the analysis of the linkage relationship of
inactivating mutations with polymorphisms showed that common alleles
are shared only by XP12PV and XP18PV and by XP13PV and XP5PV.
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As well as indicating that XPC is not essential for cell proliferation and viability, the mutation pattern in the patients has enabled us to identify a few positions in the XPC protein that are important for its functionality, namely the amino acid residue 334, mutated in the patient XP1MI, and the region around the amino acid 690–699, containing the amino acid 690 changed in XP13PV, and the insertion of an amino acid at position 698 in XP8BE (our analysis indicates that the A2815C change, resulting in Lys939Gln, described as a second putative causative mutation in XP8BE by Li et al. (12) is in fact a polymorphism).
The mutations observed in the patients result from different events and include: (a) deletions and insertions in runs of identical bases presumably resulting from replication slippage; (b) C to T transition at CpG sites, as a consequence of the demethylation of 5-methylcytosine; and (c) mutations located in the splice sites or affecting the splicing indirectly by interfering with the stability of the transcript. This would be the case for the transcript with the deletion of nts 1627–1872, found in association with a normal-sized transcript containing the C1735T transition (XP10PV) or the TG1643–1644 deletion (XP26PV). These were the only inactivating changes observed at the genomic level in XP10PV and XP26PV family members. The presence of these mutations in the 3' end of the exon 8 may interfere with the normal splicing of this unusually long (882-nt) exon, leading to the partial activation of a cryptic donor site at position 1627 and to the appearance of a transcript in which the last 246 nts of exon 8 are lost [exon 8 ends at nt 1872, as indicated by analysis in our patients and in XP22BE (13) ].
Genotype-Phenotype Relation.
A preponderance of protein truncation mutations, as seen in
XPC, has also been found in other nonessential DNA repair
genes such as XPA (24, 25, 26)
, ATM
(27)
, and, to a lesser extent, in CSB
(28
, 29)
. It raises the possibility that some missense
mutations that cause minor structural XPC alterations might result in a
milder clinical phenotype that would not be diagnosed as XP.
Conversely, in the diagnosed cases, the lack of the XPC protein and the
presence of a mutated protein both result in similar clinical
phenotypes and confer the same degree of cellular sensitivity to UV
light in terms of survival and UDS. Ten of the 12 XP-C cases reported
in this study (the 8 Italian cases, XP4BR, and XP4RO) show the clinical
features typically described in the XP-C group. As already mentioned,
XP-C is a large group, but its pathological phenotype is rather
homogeneous. The patients usually show skin and ocular symptoms,
whereas mild mental retardation has been reported for only one case
(XP1MI). Differences in the severity of skin disorders depend on age,
climate, and life-style (essentially the protection from the sun).
Accordingly, in the Italian cases, no skin tumors have been reported in
the three youngest patients.
XP6BR is an unusual patient in that he survived to the age of 66 and his multiple melanomas regressed spontaneously. He was the only patient with a large deletion in the XPC gene, but this is unlikely to be related to his clinical features because, like most of the other patients, he did not express any XPC protein in his cells (the possibility that a small amount of partially functional XPC protein, below the limit of detection in our assays, can account for these features is not excluded). XP14BR is unique in that both the patient and her cells were extremely sensitive to ionizing radiation, but this feature is unrelated to the defect in the XPC gene, because transfection with the XPC gene corrects the UV sensitivity but not the ionizing radiation sensitivity.4
All of the fourteen XP-C patients examined show varying degrees of reduction in the XPC transcript level (Refs. 12 , 13 and "Results"). The only exception is represented by patient XP13PV, who carries the missense mutation Trp690Ser on his paternal allele. Accordingly, XP13PV was the only case of the 12 analyzed by us in which the XPC protein was present, although at lower than normal levels. As already mentioned, this does not result either in milder clinical features or in a less severe cellular response to UV.
Predominant Expression of the Normal XPC Allele in
Heterozygotes.
In the 13 cell strains from heterozygous XP-C parents, the transcript
and protein levels were in the normal range. However, when we analyzed
the XPC cDNA from the parents by using standard
amplification conditions, we were unable to detect the mutations found
in the patients in any of the cases except the father of XP13PV. This
indicates that, with this one exception, the expression of the mutant
RNA in heterozygotes is much lower than that of the normal RNA. The
finding that noncoding mRNAs that carry nonsense codons are unstable is
not unprecedented (for a recent review, see Ref. 30
).
However the detection of normal levels of XPC transcript on
Northern blots suggests that, in heterozygous carriers of
XPC mutations: (a) the level of expression of the
mutated allele is lower than that of the same mutated allele in the
affected progeny; and (b) the expression of the normal
allele predominates and compensates for that of the mutated
XPC allele.
This may imply the existence of a possible mechanism of regulation of the transcript level, which is perhaps not so unexpected considering the biological role of the XPC protein (for recent reviews, see Refs. 1 , 31 ). The XPC protein is indispensable during the initial phases of GGR—the NER subpathway that repairs the damage on the nontranscribed strand of active genes and in the inactive regions of the genome. Sugasawa et al. (10) have recently termed XPC "the initiator of GGR." In association with hHR23B, XPC initiates GGR by sensing and binding to lesions and recruiting the other components of the repair apparatus. Several lines of evidence indicate that XPC is dispensable only for the repair of lesions that induce a large distortion in the DNA structure, such as an artificial cholesterol DNA adduct or damage in an "open structure" (32) . It is also not required for TCR, in which the RNA polymerase, blocked at the lesion site, serves as a damage-recognition signal. Besides being absolutely required early in the DNA damage recognition step (i.e., the limiting step of the overall process), XPC is the limiting subunit of the XPC-hHR23B complex. In vitro, hHR23B can be replaced by substituting hHR23A, the second human homologue of the yeast NER factor Rad 23, in binding and stimulating XPC activity (33, 34, 35) . In vivo, hHR23B and hHR23A are both much more abundant than XPC and mostly exist in a free form in the cells (8 , 36) . These observations suggest that it may well be that, in the presence of only one normal XPC allele, the rate of XPC transcription or the stability of the transcript is somehow up-regulated to ensure the proper and efficient functioning of GGR.
In conclusion, as well as identifying a few positions in the XPC protein that are important for its function, the results of our analysis indicate that the inactivating mutations in the XP-C patients are distributed across the gene, with no indication of any hotspots or founder effects, and mainly result in truncated proteins. This implies that XPC is not essential for cell proliferation and viabilility. In addition, we have demonstrated that, in the heterozygous carriers of XPC mutations, the expression of the normal allele predominates and compensates for that of the mutated XPC allele, which suggests the existence of a possible mechanism for monitoring the amount of the protein.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Associazione Italiana Ricerca sul
Cancro Grant (to M. S.), by EC Human Capital and Mobility Grant
CHRX-CT94-0443 (to M. S. and A. R. L.), and by EC contract
QLG1-1999-00181. 
2 To whom requests for reprints should be
addressed, at Istituto di Genetica Biochimica ed Evoluzionistica CNR,
via Abbiategrasso 207, 27100 Pavia, Italy. Phone: 39-0382-546330; Fax:
39-0382-422286; E-mail: stefanini{at}igbe.pv.cnr.it
3 The abbreviations used are: NER,
nucleotide excision repair; TCR, transcription-coupled repair; GGR,
global genome repair; XP, xeroderma pigmentosum; UDS, unscheduled DNA
synthesis; nt, nucleotide.
4 C. Arlett et al.,
unpublished results.
Received 9/23/99. Accepted 2/ 2/00.
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and the putative nuclear
location signal 
. The amino acid changes are shown boxed:
black on white, XP-C cases reported in this study;
white on gray, XP-C cases reported in Refs.