Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia

Kashiyama, Kazuya; Nakazawa, Yuka; Pilz, Daniela T.; Guo, Chaowan; Shimada, Machiko; Sasaki, Kensaku; Fawcett, Heather; Wing, Jonathan F.; Lewin, Susan O.; Carr, Lucinda; Li, Tao‐Sheng; Yoshiura, Koh-ichiro; Utani, Atsushi; Hirano, Akiyoshi; Yamashita, Shunichi; Greenblatt, Danielle; Nardò, Tiziana; Stefanini, Miria; McGibbon, David; Sarkany, Robert; Fassihi, Hiva; Takahashi, Yūzō; Nagayama, Yuji; Mitsutake, Norisato; Lehmann, Alan R.; Ogi, Tomoo

doi:10.1016/j.ajhg.2013.04.007

Cited by 188 publications

(225 citation statements)

References 35 publications

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“…Slx4 and Saw1 are proposed to function as scaffolds that assemble XPF and other structure-specific endonucleases (Lyndaker and Alani 2009;Kashiyama et al 2013;Li et al 2013;Wan et al 2013). In contrast to budding yeast (Flott et al 2007;Li et al 2008), neither slx4Δ nor saw1Δ is sensitive to UV or MMS in fission yeast (Figure S3 and (Coulon et al 2006).…”

Section: Rad16-249 Has Genetic Interactions With Other Dna Damage Repmentioning

confidence: 99%

“…Finally, we observed sensitivity to hydroxyurea (HU) in rad16-249 and rhp14Δ mutants, but again not in rad13Δ. HU causes fork stalling due to nucleotide depletion, and restart occurs via recombination-based mechanisms (Meister et al 2007;Lambert et al 2010;Sabatinos et al 2012).Slx4 and Saw1 are proposed to function as scaffolds that assemble XPF and other structure-specific endonucleases (Lyndaker and Alani 2009;Kashiyama et al 2013;Li et al 2013;Wan et al 2013). In contrast to budding yeast (Flott et al 2007;Li et al 2008), neither slx4Δ nor saw1Δ is sensitive to UV or MMS in fission yeast (Figure S3 and (Coulon et al 2006).…”

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confidence: 99%

“…In humans, mutation of XPF is associated with xeroderma pigmentosum (XP), which causes sun sensitivity and high rates of skin cancer, as well as premature aging and neurological disorders (Camenisch et al 2006;Gregg et al 2011). Recent studies suggest XPF mutations are also associated with Fanconi anemia (FA), which requires repair of interstrand crosslinks (ICLs) (Bogliolo et al 2013;Kashiyama et al 2013). The canonical model for NER suggests that upon recognition of helix-distorting lesions, the DNA is unwound to form a bubble around the damage.…”

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confidence: 99%

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Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Mastro¹,

Forsburg

2014

Genetics

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Schizosaccharomyces pombe Rad16 is the ortholog of the XPF structure-specific endonuclease, which is required for nucleotide excision repair and implicated in the single strand annealing mechanism of recombination. We show that Rad16 is important for proper completion of meiosis. In its absence, cells suffer reduced spore viability and abnormal chromosome segregation with evidence for fragmentation. Recombination between homologous chromosomes is increased, while recombination within sister chromatids is reduced, suggesting that Rad16 is not required for typical homolog crossovers but influences the balance of recombination between the homolog and the sister. In vegetative cells, rad16 mutants show evidence for genome instability. Similar phenotypes are associated with mutants affecting Rhp14 XPA but are independent of other nucleotide excision repair proteins such as Rad13 XPG . Thus, the XPF/XPA module of the nucleotide excision repair pathway is incorporated into multiple aspects of genome maintenance even in the absence of external DNA damage.T HE XPF/ERCC1 protein complex is one of several structurespecific endonucleases that function broadly as resolvases in the repair of damaged DNA (Schwartz and Heyer 2011). Rad16/Swi9 is the fission yeast ortholog of endonuclease XPF, which forms a complex with Swi10/Rad23 (ERCC1) (Carr et al. 1994). XPF has a conserved role in nucleotide excision repair (NER) to remove UV-induced lesions in the DNA (Camenisch et al. 2006;Gregg et al. 2011). In humans, mutation of XPF is associated with xeroderma pigmentosum (XP), which causes sun sensitivity and high rates of skin cancer, as well as premature aging and neurological disorders (Camenisch et al. 2006;Gregg et al. 2011). Recent studies suggest XPF mutations are also associated with Fanconi anemia (FA), which requires repair of interstrand crosslinks (ICLs) (Bogliolo et al. 2013;Kashiyama et al. 2013). The canonical model for NER suggests that upon recognition of helix-distorting lesions, the DNA is unwound to form a bubble around the damage. XPA (SpRhp14) loads XPF (SpRad16) and ERCC1 (SpSwi10); XPF cleaves at the 59 end of the bubble while XPG (SpRad13), another endonuclease, cleaves at the 39 end to remove the offending segment (Fagbemi et al. 2011;Schwartz and Heyer 2011). Thus, Schizosaccharomyces pombe rad16 mutants show a decrease in (6-4) photoproduct excision (McCready et al. 1993;Carr et al. 1994).Consistent with these clinical effects, XPF is implicated in multiple mechanisms of genome maintenance (Paques and Haber 1997;Gregg et al. 2011;Schwartz and Heyer 2011). XPF is required for single strand annealing (SSA), a form of double strand break (DSB) repair distinct from typical homologous recombination (HR) (Ma et al. 2003;Kass and Jasin 2010). This occurs when short regions of homology exposed by resection are able to pair, leaving nonhomologous 39 overhangs as substrates for XPF cleavage. In budding yeast, recruitment of ScRad1 XPF and ScRad10 ERCC1 in this pathway depends on interactions with other pro...

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Section: Rad16-249 Has Genetic Interactions With Other Dna Damage Repmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Mastro¹,

Forsburg

2014

Genetics

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“…4C). We recently described three early-onset CS patients with mutations in XPF or its partner protein ERCC1 (38).…”

Section: Xp-f (Mim278760)mentioning

confidence: 99%

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

Fassihi

Sethi

Fawcett

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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165

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Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.UV radiation | nucleotide excision repair | skin cancer | ocular disease | neurodegeneration

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“…FA is associated with congenital malformations, genome instability, and a predisposition to cancer. Genetic and functional complementation approaches have helped define 16 gene products that cooperate in a molecular pathway termed the FA pathway (3,4). This FA pathway is activated in response to cellular stress that causes interruptions in the replication or transcription processes (5).…”

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confidence: 99%

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard

Tremblay

Magron

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminalbinding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with β-catenin, and that β-catenin activation through glycogen synthase kinase 3β inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. β-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies.

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Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia

Cited by 188 publications

References 35 publications

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

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