Regulation of Transcription Elongation by the XPG-TFIIH Complex Is Implicated in Cockayne Syndrome

Narita, Takashi; Narita, Keiko; Takedachi, Arato; Saijo, Masafumi; Tanaka, Kiyoji

doi:10.1128/mcb.01401-14

Cited by 16 publications

(9 citation statements)

References 42 publications

(55 reference statements)

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“…Thus, the true biological relevance of XPC in developmental gene expression programs remains elusive. XPG–TFIIH has also been shown to interact with factors involved in transcription elongation, suggesting that defects in this association could account for certain CS features in XPG/CS patients …”

Section: Linking Ner To Transcription Demandsmentioning

confidence: 99%

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

et al. 2019

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Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate mRNA synthesis or shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed.

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Section: Linking Ner To Transcription Demandsmentioning

confidence: 99%

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

et al. 2019

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“…Xeroderma pigmentosum type G (XPG) proteins (also known as excision repair cross-complementation group 5) belong to the FEN-1 family of structure-specific nucleases and play an essential role in both NER pathways, transcription-coupled repair and global genome repair [1,[4][5][6][7][8]. Mutations in XPG proteins may also lead to the Cockayne syndrome, associated with severe developmental retardation, dwarfism and neurological abnormalities [9,10].…”

Section: Introductionmentioning

confidence: 99%

Structural and Calorimetric Studies Demonstrate that Xeroderma Pigmentosum Type G (XPG) Can Be Imported to the Nucleus by a Classical Nuclear Import Pathway via a Monopartite NLS Sequence

Barros

Takeda

Dreyer

et al. 2016

Journal of Molecular Biology

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Xeroderma pigmentosum type G (XPG) proteins are involved in DNA lesion recognition and promotion of nucleotide excision repair. Specific mutations in these proteins may lead to Cockayne syndrome, in which the patients may display severe developmental retardation and neurological abnormalities. No structural information is available for their spacer region or the C-terminal domain, which are important, respectively, for specific nucleotide excision repair activity and substrate specificity, as well as nuclear translocation. Immunofluorescence studies suggested two specific regions of the XPG C-terminus as potential bipartite nuclear localization sequences, which would be responsible for its translocation to the nucleus by the classical nuclear import pathway mediated by the importin-α (Impα). Thus, in order to test these hypotheses and gain insight into the structural basis for the nuclear import process for the XPG protein, we solved the crystal structures of complexes formed by the Impα and peptides corresponding to both putative nuclear localization signal (NLS) sequences (XPG1 and XPG2) and performed isothermal titration calorimetry assays to determine their binding affinities. Structural experiments confirm the binding of both NLS peptides to Impα but, unexpectedly, they bind to the receptor as monopartite NLSs. The isothermal titration calorimetry assays demonstrated that XPG1 and XPG2 peptides bind to two separate binding sites, but with high affinity to the major NLS-binding site of the Impα, resembling classical monopartite SV40 TAg NLS. The results lead to insights about what distinguishes monopartite and bipartite NLSs, as well as the differential roles of XPG1 and XPG2 NLSs in the nuclear localization of XPG.

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“…These studies furthermore revealed a role for Xpa and Xpf in this process ( 26 ), what we here could recapitulate: in our hands KD of Xpf and Xpa caused a similar attenuation of p21 induction as Xpg KD. Additional mechanisms may play into our observation, too, as Xpg potentially also enhances transcriptional elongation of p21 mRNA ( 39 ). Moreover, p53 target genes such as Puma are induced both by glucocorticoid treatment and IR ( 40 ).…”

Section: Discussionmentioning

confidence: 98%

Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation

Avila

Illing

et al. 2016

Nucleic Acids Res

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Reduced capacity of genome maintenance represents a problem for any organism, potentially causing premature death, carcinogenesis, or accelerated ageing. Strikingly though, loss of certain genome stability factors can be beneficial, especially for the maintenance of tissue stem cells of the intestine and the haematopoietic system. We therefore screened for genome stability factors negatively impacting maintenance of haematopoietic stem cells (HSC) in the context of ionising radiation (IR). We found that in vivo knock down of Xeroderma pigmentosum, complementation group G (Xpg) causes elevation of HSC numbers after IR treatment, while numbers of haematopoietic progenitors are elevated to a lesser extent. IR rapidly induces Xpg both on mRNA and on protein level. Prevention of this induction does not influence activation of the checkpoint cascade, yet attenuates late checkpoint steps such as induction of p21 and Noxa. This causes a leaky cell cycle arrest and lower levels of apoptosis, both contributing to increased colony formation and transformation rates. Xpg thus helps to adequately induce DNA damage responses after IR, thereby keeping the expansion of damaged cells under control. This represents a new function of Xpg in the response to IR, in addition to its well-characterized role in nucleotide excision repair.

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Regulation of Transcription Elongation by the XPG-TFIIH Complex Is Implicated in Cockayne Syndrome

Cited by 16 publications

References 42 publications

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Structural and Calorimetric Studies Demonstrate that Xeroderma Pigmentosum Type G (XPG) Can Be Imported to the Nucleus by a Classical Nuclear Import Pathway via a Monopartite NLS Sequence

Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation

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