| Publication number |
CLPUB00565 |
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| Authors |
Khan S.G., Oh K.-S., Inui H., Emmert S., Tamura D., DiGiovanna J.J., Shahlavi T., Baker C.C., Schneider T.D., Kraemer K.H. |
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| Title |
Impaired lariat-loop formation causing abnormal XPC pre-mRNA splicing resulted in xeroderma pigmentosum. |
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| Citation |
J. Invest. Dermatol. 129 Suppl. 1:S28-S28(2009) |
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| Abstract |
The lariat-loop formation involving branch point sequence (BPS) near the
3'end of introns is crucial for precise processing of the pre-mRNA. We
previously reported that mutations within -4 and -24 branch point
sequences (BPS) in intron3 of the XPC gene differentially affects the XPC
premRNA splicing by disrupting lariat-loop formation in xeroderma
pigmentosum (XP) patients (Hum. Mol. Genetics, 13: 343 (2004)). Here we
studied two related XP patients, XP14BE and XP377BE, with multiple skin
cancers and reduced DNA repair. Their cells had the same 9 base-pair
deletion (-13 to -21) that lies 3 bases downstream of the -25 'A' of the
mapped BPS in intron6 of the XPC gene. This deletion mutation moved the
BPS closer to intron6/exon7 junction and abolished lariat-loop formation.
This change reduced the information content of the intron6 splice acceptor
from 12.3 to 6.2 bits. These cells exclusively expressed XPC mRNA with an
in-frame exon7 deletion. The cells had reduced amounts of mutant XPC
protein. This mutation abolished DNA repair activity since an expression
vector containing XPC cDNA devoid of exon 7 failed to correct DNA repair
defect in other XP-C cells in a post-UV host cell reactivation assay. The
mutant XPC protein did not localize to UV-induced DNA-lesions in the
patient's cells. Thus, the 30 amino acid sequence derived from exon 7 of
the XPC gene is an important motif for localization of XPC protein to the
site of damaged-DNA. Abolishing lariat-loop formation resulted in
expression of mutant XPC protein with reduced nucleotide excision repair
function that resulted in multiple sunlight-induced skin cancers in these
XP-C patients.
|
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| Cell lines |
CVCL_U671; XP14BE CVCL_ZS41; XP377BE |
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