Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

Spiro, Craig; McMurray, Cynthia T.

doi:10.1128/mcb.23.17.6063-6074.2003

Cited by 74 publications

(70 citation statements)

References 71 publications

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“…Among the 20 genes shown to affect CAG repeat contraction in human cells (6,27,28,31,32,37), six have been tested in a mouse model and also shown to modulate CAG repeat instability, including MSH2 (22,47,48), MSH3 (52), PMS2 (12), DNMT1 (6), CSB (20), and XPA (L. Hubert et al, unpublished data). Similarly, among those genes with little effect on CAG contraction in human cells (28), three have been tested in mouse models and shown to have little effect on CAG repeats, including MSH6 (52), XPC (8), and FEN1 (50,51). Interestingly, only in the case of the OGG1 glycosylase discussed below do the results differ, with deficiencies having no effect on CAG contraction in human cells (32), but large effects in mice (21).…”

Section: Discussionmentioning

confidence: 81%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately highthroughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phosphodiesterase 1 (TDP1), and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions. The TOP1-TDP1-SSBR pathway normally functions to suppress repeat instability, since interfering with it stimulated repeat contractions. We further showed that the increase in repeat contractions when the TOP1-TDP1-SSBR pathway is compromised arises via transcription-coupled nucleotide excision repair, a previously identified contributor to transcription-induced repeat instability. These studies broaden the scope of pathways involved in transcription-induced CAG repeat instability and begin to define their interrelationships.

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Section: Discussionmentioning

confidence: 81%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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“…Among several DNA repair pathways, it has been extensively studied that excision repair crosscomplementation group 1 (ERCC1) has the critical role in nucleotide excision repair pathway and high ERCC1 ZNF143 and cisplatin resistance T Wakasugi et al expression is associated with cisplatin resistance (Altaha et al, 2004). Both BRCA1 and Rad51 have been shown to be involved in recombinational repair and also associated with cisplatin resistance (Bhattacharyya et al, 2000;Spiro and McMurray, 2003). The FEN-1 is a 5 0 endonuclease and has been implicated in various DNA repair processes (Lieber, 1997).…”

Section: Discussionmentioning

confidence: 99%

ZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes

et al. 2007

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Zinc-finger protein 143 (ZNF143) is a human homolog of Xenopus transcriptional activator staf that is involved in selenocystyl tRNA transcription. We previously showed that ZNF143 expression is induced by treatment with DNA-damaging agents and that it preferentially binds to cisplatin-modified DNA. In this study, the potential function of ZNF143 was investigated. ZNF143 was overexpressed in cisplatin-resistant cells. ZNF143 knockdown in prostate cancer caused increased sensitivity for cisplatin, but not for oxaliplatin, etoposide and vincristine. We also showed that ZNF143 is associated with tumor suppressor gene product p73 but not with p53. p73 could stimulate the binding of ZNF143 to both ZNF143 binding site and cisplatin-modified DNA, and modulate the function of ZNF143. We provide a direct evidence that both Rad51 and flap endonuclease-1 are target genes of ZNF143 and overexpressed in cisplatin-resistant cells. Taken together, these experiments demonstrate that an interplay of ZNF143, p73 and ZNF143 target genes is involved in DNA repair gene expression and cisplatin resistance.

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“…For instance, flap endonuclease 1 required for normal maturation of Okazaki fragments during replication fails to process flaps folded into aberrant hairpin structures and is thought to cause expansion at CAG repeats. 26,27 Alternatively, an independent de novo event may have occurred in a single person 6300 years ago, which affected the fidelity of DNA polymerase or a DNA mismatch repair enzyme, which in conjunction with the unstable repeat region resulted in the HREM. 28,29 Role of the HREM in ALS and FTLD biology The dominant pathology in 90% of ALS and tau-negative FTD inclusions contain the TAR DNA-binding protein (TDP-43) within the cytoplasm of neurons and glia.…”

Section: Human_reference : Gcgcgctaggggccggggccggggcc---------------mentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS þ / ÀFTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

Cited by 74 publications

References 71 publications

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

ZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

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