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Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.

ABSTRACT: Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD gene. We discovered large differences in nucleotide excision repair (NER) protein recruitment to sites of localized UV damage in TTD cells compared to XP or normal cells. XPC protein was rapidly localized in all cells. XPC was redistributed in TTD, and normal cells by 3 hr postirradiation, but remained localized in XP cells at 24-hr postirradiation. In XP cells recruitment of other NER proteins (XPB, XPD, XPG, XPA, and XPF) was also delayed and persisted at 24 hr (p<0.001). In TTD cells with defects in the XPD, XPB, or GTF2H5 (TTDA) genes, in contrast, recruitment of these NER proteins was reduced compared to normals at early time points (p<0.001) and remained low at 24 hr postirradiation. These data indicate that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increased skin cancer.

SUBMITTER: Boyle J

PROVIDER: S-EPMC3477783 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.

Boyle Jennifer J Ueda Takahiro T Oh Kyu-Seon KS Imoto Kyoko K Tamura Deborah D Jagdeo Jared J Khan Sikandar G SG Nadem Carine C Digiovanna John J JJ Kraemer Kenneth H KH

Human mutation 20081001 10

Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD ge ...[more]

PMID: 18470933

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Project description:BackgroundRetrotransposition of protein-coding genes is thought to occur due to the existence of numerous processed pseudogenes in both animals and plants. Unlike retrotransposons including Alu and LINE-1, direct evidence of such retrotransposition events has not been reported to date. Even if such an event occurs in a somatic cell, it is almost impossible to detect it using bulk of cells as a sample. Single-cell analyses or other techniques are needed.MethodsIn order to examine genetic stability of stem cells, we have established induced pluripotent stem cell (iPSC) lines from several patients with DNA repair-deficiency disorders, such as ataxia telangiectasia and xeroderma pigmentosum, along with healthy controls. Performing whole-exome sequencing analyses of these parental and iPSC lines, we compiled somatic mutations accumulated by the deficiency of DNA repair mechanisms. Whereas most somatic mutations cannot be detected in bulk, cell reprogramming enabled us to observe all the somatic mutations which had occurred in the cell line. Patterns of somatic mutations should be distinctive depending on which DNA repair gene is impaired.ResultsThe comparison revealed that deficiency of ATM and XPA preferentially gives rise to indels and single-nucleotide substitutions, respectively. On the other hand, deficiency of ERCC2 caused not only single-nucleotide mutations but also many retrotranspositions of endogenous genes, which were readily identified by examining removal of introns in whole-exome sequencing. Although the number was limited, those events were also detected in healthy control samples.ConclusionsThe present study exploits clonality of iPSCs to unveil somatic mutation sets that are usually hidden in bulk cell analysis. Whole-exome sequencing analysis facilitated the detection of retrotransposition mutations. The results suggest that retrotranspositions of human endogenous genes are more frequent than expected in somatic cells and that ERCC2 plays a defensive role against transposition of endogenous and exogenous DNA fragments.

Dataset Information

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.

Publications

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.

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