Pontin and Reptin, Two Related ATPases with Multiple Roles in Cancer

Huber, Otmar; Ménard, Ludovic; Haurie, Valérie; Nicou, Alexandra; Taras, Danièle; Rosenbaum, Jean

doi:10.1158/0008-5472.can-08-0547

Cited by 96 publications

(93 citation statements)

References 25 publications

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“…For example, reptin [also known as RuvB-like (RUVBL) 2] and pontin (RUVBL1) have been demonstrated to be overexpressed in several tumors (5). These proteins interact with c-Myc or β-catenin, thus modulating their transcriptional activities to promote tumor progression (6). AAA+ proteins hydrolyze ATP, and thus, chemical inhibitors that disrupt the activities of cancer-associated AAA+ proteins may represent promising anti-cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

et al. 2016

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Abstract. Thyroid hormone receptor interactor 13 (TRIP13) is a member of the ATPases associated with various cellular activities family of proteins and is highly conserved in a wide range of species. Recent studies have demonstrated that TRIP13 is critical for the inactivation of the spindle assembly checkpoint and is associated with the progression of certain cancers. In the present study, the role of TRIP13 in colorectal cancer (CRC) was examined. Reverse transcription-quantitative polymerase chain reaction analysis revealed that TRIP13 messenger RNA was highly expressed in multiple CRC tissues. The depletion of TRIP13 in CRC cells suppressed cell proliferation, migration and invasion. To determine whether the catalytic activity of TRIP13 was critical for cancer progression, an inactive mutant of TRIP13 was expressed in CRC cells. The invasion of cancer cells that expressed the mutant TRIP13 was significantly reduced compared with that of the wild type TRIP13-expressing cancer cells. These results indicate that TRIP13 could be a potential target for CRC treatment. IntroductionThe ATPases associated with various cellular activities (AAA+) family of proteins comprises a functionally different group of enzymes that are involved in an array of cellular processes, including protein degradation, protein-complex disassembly and DNA replication (1). The AAA+ proteins are present in all kingdoms, and are characterized by the presence of conserved AAA+ domains that contain Walker A and Walker B motifs, followed by a conserved region called second region of homology (2). The majority of AAA+ proteins form hexamers to exert their biological functions. The chemical energy generated by adenosine triphosphate (ATP) hydrolysis by this family of proteins induces conformational changes in the substrate proteins to modulate their functions (3,4).A previous study reported that certain AAA+ enzymes are associated with tumor progression (5). For example, reptin [also known as RuvB-like (RUVBL) 2] and pontin (RUVBL1) have been demonstrated to be overexpressed in several tumors (5). These proteins interact with c-Myc or β-catenin, thus modulating their transcriptional activities to promote tumor progression (6). AAA+ proteins hydrolyze ATP, and thus, chemical inhibitors that disrupt the activities of cancer-associated AAA+ proteins may represent promising anti-cancer drugs.Thyroid hormone receptor interactor 13 (TRIP13, also known as 16E1BP and pachytene checkpoint 2) is a member of the AAA+ family proteins and is conserved in a wide range of species (7). It was first identified as a protein that interacts with human papilloma virus E1 proteins by a yeast two-hybrid analysis, but the physiological function of the interaction remains unknown (7). Accumulating studies have demonstrated that TRIP13 plays pivotal roles in meiotic recombination and DNA repair in plants, yeast, worms and mice (8-12). TRIP13 forms a stable hexameric ring, and ATP binding, as well as ATP hydrolysis, are critical for the function of the protein (13). Previous...

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Section: Introductionmentioning

confidence: 99%

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

et al. 2016

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“…1E; Cheung et al 2010;Gorynia et al 2011). The importance of pontin and reptin to human health is indicated by their overexpression in several cancers including hepatocellular carcinoma, colon and bladder cancer, and melanoma (Huber et al 2008;Jha and Dutta 2009). Despite this plethora of information on pontin and reptin over the past 15 years, no mechanistic insight has been gained on their role in any of these complexes or processes.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs

Machado-Pinilla

Liger

Leulliot

et al. 2012

RNA

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The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes.

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“…In one clear example, yeast RVBs are required for the proper assembly of functional INO80.com (7), as the lack of RVBs results in depletion of ARP5, an essential subunit of INO80.com, from the complex. The importance of RVBs in cancer has been highlighted by recent discoveries showing overexpression of the proteins in hepatocellular carcinomas (15) and an important role in the regulation of metastasis (16,17).…”

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confidence: 99%

RVBs Are Required for Assembling a Functional TIP60 Complex

Jha

Gupta

Dar

et al. 2013

Molecular and Cellular Biology

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RVB1/RVB2 (RuvBL1/RuvBL2 or pontin/reptin) are enigmatic AAA ؉ ATPase proteins that are present in multiple cellular complexes. Although they have been implicated in many cellular functions, the exact molecular function of RVB proteins in the various complexes is not clear. TIP60 complex (TIP60.com) is a tumor suppressor chromatin-remodeling complex containing RVB proteins. RVBs are required for the lysine acetyltransferase activity of TIP60.com but not for that of the pure recombinant TIP60 polypeptide. Here we describe two molecular functions of RVBs in TIP60.com. First, RVBs negate the repression of catalytic activity of TIP60 by another protein in TIP60.com, p400. RVBs competitively displace the SNF2 domain of p400 from the TIP60 polypeptide. In addition RVBs are also required for heat stability of TIP60.com by a p400-independent pathway. RVB1 and RVB2 are redundant with each other for these functions and do not require their ATPase activities. Thus, RVB proteins act as molecular adaptors that can substitute for one another to facilitate the optimal assembly, heat stability, and function of the TIP60 complex.

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Pontin and Reptin, Two Related ATPases with Multiple Roles in Cancer

Cited by 96 publications

References 25 publications

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs

RVBs Are Required for Assembling a Functional TIP60 Complex

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