Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

I, Abramowicz; Carpenter, Gillian; Alfieri, Mariaevelina; Colnaghi, Rita; Outwin, Emily; Parent, Philippe; Thauvin‐Robinet, Christel; Iaconis, Daniela; Franco, Brunella; O’Driscoll, Mark

doi:10.1093/hmg/ddw364

Cited by 12 publications

(9 citation statements)

References 94 publications

(24 reference statements)

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“…In serum‐deprived cells, removal of OFD1 from centriolar satellites through the autophagy machinery is required for the onset of ciliogenesis (Tang et al, 2013). A role for OFD1 in non‐ciliary pathways has also been reported (Abramowicz et al, 2017; Iaconis et al, 2017; Alfieri et al, 2020). The ubiquitin‐proteasome system (UPS) controls the levels of ciliary regulatory proteins, contributing to the dynamic assembly/disassembly of the primary cilium (Kasahara et al, 2014; Liu et al, 2014; Wheway et al, 2015; Kwon & Ciechanover, 2017; Nagai et al, 2018; Tsai et al, 2019; Wiegering et al, 2019).…”

Section: Introductionmentioning

confidence: 70%

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

Senatore¹,

Chiuso²,

Rinaldi³

et al. 2021

The EMBO Journal

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The primary cilium is a microtubule‐based sensory organelle that dynamically links signalling pathways to cell differentiation, growth, and development. Genetic defects of primary cilia are responsible for genetic disorders known as ciliopathies. Orofacial digital type I syndrome (OFDI) is an X‐linked congenital ciliopathy caused by mutations in the OFD1 gene and characterized by malformations of the face, oral cavity, digits and, in the majority of cases, polycystic kidney disease. OFD1 plays a key role in cilium biogenesis. However, the impact of signalling pathways and the role of the ubiquitin‐proteasome system (UPS) in the control of OFD1 stability remain unknown. Here, we identify a novel complex assembled at centrosomes by TBC1D31, including the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1. We show that TBC1D31 is essential for ciliogenesis. Mechanistically, upon G‐protein‐coupled receptor (GPCR)‐cAMP stimulation, PKA phosphorylates OFD1 at ser735, thus promoting OFD1 proteolysis through the praja2‐UPS circuitry. This pathway is essential for ciliogenesis. In addition, a non‐phosphorylatable OFD1 mutant dramatically affects cilium morphology and dynamics. Consistent with a role of the TBC1D31/praja2/OFD1 axis in ciliogenesis, alteration of this molecular network impairs ciliogenesis in vivo in Medaka fish, resulting in developmental defects. Our findings reveal a multifunctional transduction unit at the centrosome that links GPCR signalling to ubiquitylation and proteolysis of the ciliopathy protein OFD1, with important implications on cilium biology and development. Derangement of this control mechanism may underpin human genetic disorders.

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Section: Introductionmentioning

confidence: 70%

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

Senatore¹,

Chiuso²,

Rinaldi³

et al. 2021

The EMBO Journal

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“…OFD1 is involved in the control of centrioles length and distal structure (Singla et al, 2010); chromatin remodeling at DNA double strand breaks (Abramowicz et al, 2016), protein quality balance (Amato, Morleo, Giaquinto, di Bernardo, & Franco, 2014;Iaconis et al, 2017;Liu et al, 2014), and cell cycle progression (Alfieri et al, 2020). More recently, a role for OFD1 as a novel receptor in selective autophagy has also been described .…”

Section: The Ofd1 Proteinmentioning

confidence: 99%

“…Additional functions not confined to the suppression or promotion of ciliogenesis have been ascribed to the OFD1 protein (Morleo & Franco, 2020 ). OFD1 is involved in the control of centrioles length and distal structure (Singla et al, 2010 ); chromatin remodeling at DNA double strand breaks (Abramowicz et al, 2016 ), protein quality balance (Amato, Morleo, Giaquinto, di Bernardo, & Franco, 2014 ; Iaconis et al, 2017 ; Liu et al, 2014 ), and cell cycle progression (Alfieri et al, 2020 ). More recently, a role for OFD1 as a novel receptor in selective autophagy has also been described (Franco & Morleo, 2021 ; Morleo et al, 2021 ; Morleo & Franco, 2021 ).…”

Section: The Ofd1 Proteinmentioning

confidence: 99%

OFD1: One gene, several disorders

Pezzella

Bove

Tammaro

et al. 2022

American J of Med Genetics Pt C

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The OFD1 protein is necessary for the formation of primary cilia and left–right asymmetry establishment but additional functions have also been ascribed to this multitask protein. When mutated, this protein results in a variety of phenotypes ranging from multiorgan involvement, such as OFD type I (OFDI) and Joubert syndromes (JBS10), and Primary ciliary dyskinesia (PCD), to the engagement of single tissues such as in the case of retinitis pigmentosa (RP23). The inheritance pattern of these condition differs from X‐linked dominant male‐lethal (OFDI) to X‐linked recessive (JBS10, PCD, and RP23). Distinctive biological peculiarities of the protein, which can contribute to explain the extreme clinical variability and the genetic mechanisms underlying the different disorders are discussed. The extensive spectrum of clinical manifestations observed in OFD1‐mutated patients represents a paradigmatic example of the complexity of genetic diseases. The elucidation of the mechanisms underlying this complexity will expand our comprehension of inherited disorders and will improve the clinical management of patients.

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“…Recently, some cilia proteins have been found to be important in DDR, including but not limited to: NEK1, [128] NEK8, [129] MRE11, [130] ZNF423, [130] CEP164, [130,131] and OFD1. [132] Lack of knowledge regarding the role of DDR enzymes and cilia makes it difficult to understand how these proteins may fit in our polarity hypothesis. Some of the examples above are easy to explain within our model.…”

Section: Caveatsmentioning

confidence: 99%

Primary Cilia Reconsidered in the Context of Ciliopathies: Extraciliary and Ciliary Functions of Cilia Proteins Converge on a Polarity theme?

Hua

Ferland

2018

BioEssays

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Once dismissed as vestigial organelles, primary cilia have garnered the interest of scientists, given their importance in development/signaling, and for their implication in a new disease category known as ciliopathies. However, many, if not all, "cilia" proteins also have locations/functions outside of the primary cilium. These extraciliary functions can complicate the interpretation of a particular ciliopathy phenotype: it may be a result of defects at the cilium and/or at extraciliary locations, and it could be broadly related to a unifying cellular process for these proteins, such as polarity. Assembly of a cilium has many similarities to the development of other polarized structures. This evolutionarily preserved process for the assembly of polarized cell structures offers a perspective on how the cilium may have evolved. We hypothesize that cilia proteins are critical for cell polarity, and that core polarity proteins may have been specialized to form various cellular protrusions, including primary cilia.

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Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

Cited by 12 publications

References 94 publications

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

OFD1: One gene, several disorders

Primary Cilia Reconsidered in the Context of Ciliopathies: Extraciliary and Ciliary Functions of Cilia Proteins Converge on a Polarity theme?

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