MMXD, a TFIIH-Independent XPD-MMS19 Protein Complex Involved in Chromosome Segregation

Ito, Shinsuke; Tan, Li Jing; Andoh, Daisuke; Narita, Takashi; Seki, Mineaki; Hirano, Yasuhiro; Narita, Keiko; Kuraoka, Isao; Hiraoka, Yasushi; Tanaka, Kiyoji

doi:10.1016/j.molcel.2010.07.029

Cited by 101 publications

(146 citation statements)

References 28 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…The XPD helicase functions as a component of TFIIH but also can be found associated with non-TFIIH complexes that play roles in processes other than transcription and DNA repair. The MMXD complex is composed of XPD, MMS19, MIP18, Ciao1, and ANT2 and is involved in chromosome segregation and nuclear-shape formation (49). XPD also associates with CAK in the absence of the other TFIIH subunits, regulating the localization of CAK on its substrate and therefore its activity (50).…”

Section: Discussionmentioning

confidence: 99%

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

Abdulrahman

Iltis

Radu

et al. 2013

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

View full text Add to dashboard Cite

The xeroderma pigmentosum group D (XPD) helicase is a subunit of transcription/DNA repair factor, transcription factor II H (TFIIH) that catalyzes the unwinding of a damaged DNA duplex during nucleotide excision repair. Apart from two canonical helicase domains, XPD is composed of a 4Fe-S cluster domain involved in DNA damage recognition and a module of uncharacterized function termed the "ARCH domain." By investigating the consequences of a mutation found in a patient with trichothiodystrophy, we show that the ARCH domain is critical for the recruitment of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. Indeed, this mutation not only affects the interaction with the MAT1 CAK subunit, thereby decreasing the in vitro basal transcription activity of TFIIH itself and impeding the efficient recruitment of the transcription machinery on the promoter of an activated gene, but also impairs the DNA unwinding activity of XPD and the nucleotide excision repair activity of TFIIH. We further demonstrate the role of CAK in downregulating the XPD helicase activity within TFIIH. Taken together, our results identify the ARCH domain of XPD as a platform for the recruitment of CAK and as a potential molecular switch that might control TFIIH composition and play a key role in the conversion of TFIIH from a factor active in transcription to a factor involved in DNA repair.rare disease | regulation of gene expression T he xeroderma pigmentosum group D (XPD) gene encodes a 5′-3′ helicase (XPD) that harbors mutations in patients suffering from three rare autosomal recessive diseases, xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne syndrome (CS) (1, 2). XP is characterized by a deficit of the nucleotide excision repair (NER) pathway, leading to sun sensitivity and susceptibility to skin cancer. TTD is characterized by sulfur-deficient brittle hair and a variety of neuroectodermal symptoms (3). XPD is the founding member of a family of DNA helicases conserved in archaea and eukaryotes. All family members share a four-domain organization including a conserved (Fe-S) cluster-binding domain that is essential for the helicase activity and a module of uncharacterized function named the ARCH domain by its arch-shape structure (4-7). Although archeal XPD homologs are monomers and have no known stable interactors, eukaryotic XPD homologs are part of the general transcription/DNA repair factor transcription factor II H (TFIIH), a multisubunit complex made up of 10 subunits (reviewed in ref. 8). Low-resolution models for TFIIH have been obtained for the complex in yeast (9, 10) and for the human complex (11), showing an overall conservation of shape. Human TFIIH can be resolved into two functional and structural entities bridged by XPD: the core-TFIIH consists of XPB, p62, p52, p44, p34, and p8, whereas the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex contains CDK7, cyclin H, and ménage a trois 1 (MAT1). XPD interacts with the p44 core-TFIIH subunit and with MAT1, a subunit of CAK involve...

show abstract

Section: Discussionmentioning

confidence: 99%

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

Abdulrahman

Iltis

Radu

et al. 2013

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

View full text Add to dashboard Cite

show abstract

“…Purification of Protein Complexes-The FLAG-His 6 -MMS19 complex was purified from HEK293 cells overexpressing FLAG-His 6 -MMS19 as described previously (17). The complex between FLAG-His 6 -MMS19 and HA-CIAO1 was purified by sequential affinity purification with anti-FLAG M2-agarose (Sigma-Aldrich), followed by anti-HA agarose (Sigma-Aldrich), as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we reported that human MMS19 and XPD form a novel TFIIH-independent protein complex, which we named MMXD, consisting of MMS19, XPD, MIP18, ANT2, and CIAO1 (17). CIAO1 is involved in the late step of cytosolic iron-sulfur cluster assembly (CIA) (18).…”

mentioning

confidence: 99%

IOP1 Protein Is an External Component of the Human Cytosolic Iron-Sulfur Cluster Assembly (CIA) Machinery and Functions in the MMS19 Protein-dependent CIA Pathway

Seki

Takeda

Iwaï

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:The CIA machinery in human cells is unclear.Results: MMS19 formed a complex with MIP18, CIAO1, and IOP1, but IOP1 behaved differently from the other components. Conclusion: The CIA complex consists of a core MMS19-MIP18-CIAO1 complex, and IOP1 is an external component of the CIA machinery. Significance: This study increases the understanding of the composition of the CIA machinery in human cells and the interactions between the components.

show abstract

“…Thus, miRNAs targeting TFIIHcoding mRNAs could, in principle, modulate the availability of different subunits favoring the formation of differential TFIIHderived subcomplexes. Supporting the notion that different subcomplexes coexist, it has been recently shown that the XPD subunit is part of a different complex, termed MMXD (38), involved in chromosomal segregation. In addition, it has been shown that members of the proteosome pathway interact with particular CAK components regulating its degradation (39).…”

Section: Discussionmentioning

confidence: 94%

MicroRNA-27a regulates basal transcription by targeting the p44 subunit of general transcription factor IIH

Portal

2011

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

View full text Add to dashboard Cite

General transcription factor IIH (TFIIH) is a complex RNA polymerase II basal transcription factor comprising 10 different polypeptides that display activities involved in transcription and DNA repair processes. Although biochemical studies have uncovered TFIIH importance, little is known about how the mRNAs that code for TFIIH subunits are regulated. Here it is shown that mRNAs encoding seven of the TFIIH subunits (p34, p44, p52, p62, XPB, CDK7, and p8) are regulated at the posttranscriptional level in a Dicer-dependent manner. Indeed, abolition of the miRNA pathway induces abnormal accumulation, stabilization, and translational activation of these seven mRNAs. Herein, miR-27a was identified as a key regulator of p44 mRNA. Moreover, miR-27a was shown to destabilize the p44 subunit of the TFIIH complex during the G2-M phase, thereby modulating the transcriptional shutdown observed during this transition. This work is unique in providing a demonstration of global transcriptional regulation through the action of a single miRNA.T o maintain cellular homeostasis, cells have evolved a myriad of specialized pathways, among which basal transcription and DNA repair play crucial roles. Both mechanisms are mainly regulated by the multisubunit complex termed TFIIH (general transcription factor IIH) formed by two modules, the core and the CAK [cyclin-dependent kinase (CDK)-activated kinase], each displaying distinguishable activities and differential protein composition (1-3). Whereas the core is constituted by seven polypeptides (p34, p44, p52, p62, XPB, XPD, and p8) and is indispensable for transcription and DNA repair (4), the CAK contains only three proteins (CDK7, CycH, and MAT1) and is required to modulate transcription by phosphorylating the carboxyl terminal domain of RNA polymerase II (5). Moreover, the CAK module regulates cellcycle progression by phosphorylating CDKs during G2-M transition in an autonomous fashion (6).Mutations in different TFIIH subunits lead to severe clinical disorders that range from mental retardation to cancer predisposition. This predisposition is manifested in patients displaying three clinically well-characterized syndromes-Xeroderma Pigmentosum, Cockaine syndrome, and Trichothiodystrophyhighlighting the importance of maintaining TFIIH integrity (7-9). Lessons learned from mutations encountered on patients helped to unravel which activities of TFIIH were modified in different clinical contexts. However, it has not been possible either to link specific mutations with a particular syndrome or with clinical severity (10-12). Nevertheless, all three clinical anomalies are taught, in principle, to be caused by diminished transcriptional and DNA repair activities often associated with reduced TFIIH stability. In vitro-obtained data show that naturally occurring mutations in XPD or p44 that alter the XPD/p44 or p44/p62 interaction may affect the composition of TFIIH by decreasing levels of XPD and CAK subunits associated with the core. On the other hand, mutations in XPB and p52 may prevent XPB...

show abstract

MMXD, a TFIIH-Independent XPD-MMS19 Protein Complex Involved in Chromosome Segregation

Cited by 101 publications

References 28 publications

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

IOP1 Protein Is an External Component of the Human Cytosolic Iron-Sulfur Cluster Assembly (CIA) Machinery and Functions in the MMS19 Protein-dependent CIA Pathway

MicroRNA-27a regulates basal transcription by targeting the p44 subunit of general transcription factor IIH

Contact Info

Product

Resources

About