# LRDD

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**[Leucine-rich repeats](/source/Leucine-rich_repeats) and [death domain](/source/Death_domain) containing**, also known as **LRDD** or [p53](/source/P53)-induced protein with a [death domain](/source/Death_domain) (PIDD), is a [protein](/source/Protein) which in humans is encoded by the *LRDD* [gene](/source/Gene).[1]

The [leucine-rich repeat](/source/Leucine-rich_repeat) (LRR), first identified by Patthy,[2] is a [domain](/source/Protein_domain) involved in [protein-protein interactions](/source/Protein-protein_interactions) and is present in numerous [proteins](/source/Proteins) that serve a variety of cellular roles.[3] [Leucine-rich repeats](/source/Leucine-rich_repeats) (LRR) [proteins](/source/Proteins) in [eukaryotic cells](/source/Eukaryotic_cells) are found in the [nucleus](/source/Cell_nucleus), [cytoplasm](/source/Cytoplasm), [extracellular matrix](/source/Extracellular_matrix) and [plasma membrane](/source/Plasma_membrane).[4]

## The identification of PIDD1

PIDD, now officially known as PIDD1 (p53-induced [death domain](/source/Death_domain) [protein](/source/Protein) 1), a transformation of name was necessary to avoid confusion with primary [immune deficiency](/source/Immune_deficiency) disorders, which are often abbreviated similarly in scientific literature. Notably, no PIDD1 orthologues have been identified in non-vertebrates, and PIDD1 paralogues have not been found in vertebrates. Initially, PIDD1 was also referred to as [leucine-rich repeat](/source/Leucine-rich_repeat) and [death domain](/source/Death_domain) containing [protein](/source/Protein) (LRDD) and was independently reported by two research groups in 2000.[5][6]

### Death domain

Telliez and colleagues, in a [bioinformatics](/source/Bioinformatics) search for [proteins](/source/Proteins) possessing a [death domain](/source/Death_domain) that resembles the one found in [human](/source/Human) receptor-interacting serine/threonine [kinase](/source/Kinase) 1 (RIPK1, also known as RIP1), discovered a [protein](/source/Protein) and named it LRDD based on its structural characteristics.[7] Through [sequence analysis](/source/Sequence_analysis), it was discovered to contain [leucine-rich repeats](/source/Leucine-rich_repeats) (LRRs) at the [N-terminal](/source/N-terminal) region, ZU5 [domains](/source/Protein_domain) (found in ZO-1 and Unc5-like netrin receptors) in the middle section, and a [death domain](/source/Death_domain) (DD) at the [C-terminus](/source/C-terminus). Additionally, a [structural domain](/source/Structural_domain) referred to as the uncharacterized [protein domain](/source/Protein_domain) in UNC5, PIDD, and ankyrins (UPA) was also identified between the ZU5 domain and the [death domain](/source/Death_domain) (DD).[8]

### Differential display analysis

Also, a [differential display](/source/Differential_display) analysis conducted in an [erythroleukaemia](/source/Erythroleukaemia) [cell line](/source/Cell_line) by Lin and co-researchers discovered that PIDD1 is a direct transcriptional target of [p53](/source/P53).[9] Furthermore, PIDD1 overexpression inhibited cell growth by triggering [apoptosis](/source/Apoptosis) in [p53](/source/P53)-deficient cells, an effect that was reversed when PIDD1 was knocked down. This led to the assumption that PIDD1 plays a critical role in the [apoptotic pathway](/source/Apoptotic_pathway) regulated by [p53]].[10] In [p53](/source/P53)-deficient [HCT116](/source/HCT116) and [HEK293](/source/HEK293) cells which express the large [T antigen](/source/T_antigen), a basal level of PIDD1 expression was observed. This finding suggests that PIDD1 may play roles beyond its traditional involvement in the [p53](/source/P53)-mediated [DNA damage](/source/DNA_damage) response.[11][12]

## Structure of PIDD1

### Death fold

[Proteins](/source/Proteins) with a [death domain](/source/Death_domain) (DD), such as PIDD1, are defined by a structural framework consisting of six α-helical bundles, referred to as a '[death fold](/source/Death_fold)'.

This structure is also present in other [proteins](/source/Proteins) that contain [domains](/source/Protein_domain) like the [caspase recruitment domain](/source/Caspase_recruitment_domain) (CARD), [death effector domain](/source/Death_effector_domain) (DED), [pyrin domain](/source/Pyrin_domain) (PYD), or combinations of these motifs (e.g., DD/CARD, DD/DED, PYRIN/CARD). These death folds facilitate homotypic protein-protein interactions (such as DD/DD or CARD/CARD), enabling the formation of large multi-protein signaling complexes. Notable examples include the [apoptosome](/source/Apoptosome), which contains apoptotic protease-activating factor 1 (APAF1) and [caspase-9](/source/Caspase-9), and the death-inducing signaling complex (DISC) associated with [caspase-8](/source/Caspase-8) and members of the [tumor necrosis factor receptor](/source/Tumor_necrosis_factor_receptor) (TNFR) superfamily.[13]

### Parts and cleavages

[Transcript variant](/source/Transcript_variant) 1 of PIDD1 [mRNA](/source/MRNA) in [humans](/source/Humans), produces a full-length PIDD1 [protein](/source/Protein) consisting of 910 [amino acids](/source/Amino_acids), with a molecular weight of about 100 kDa. This [protein](/source/Protein) can be broken down into three parts: a 48 kDa [N-terminal](/source/N-terminal) fragment called PIDD-N, and two [C-terminal](/source/C-terminal) fragments, PIDD-C (51 kDa) and PIDD-CC (37 kDa). These cleavages occur at positions S446 and S588 through an [autoproteolytic](/source/Autoproteolytic) process that resembles [proteins](/source/Proteins) like inteins or [nucleoporin](/source/Nucleoporin) Nup98 undergo self-cleavage.[14] These [proteins](/source/Proteins) contain a conserved HSF [tripeptide](/source/Tripeptide) framework that enables a [hydrophilic](/source/Hydrophilic) attack of the hydroxyl-group within the serine residue on the preceding [peptide bond](/source/Peptide_bond), converting it into an [ester bond](/source/Ester_bond) that is susceptible to cleavage by an additional [nucleophile](/source/Nucleophile).[15][16][17]

The cleavage of full-length PIDD1 (FL-PIDD1) into PIDD-C or PIDD-CC seems to occur constitutively, meaning it happens regularly, which makes FL-PIDD1 levels remain low even when [p53is](/source/P53) activated. However, the observation that PIDD-C accumulates before PIDD-CC in response to [DNA damage](/source/DNA_damage) supports the idea that PIDD-C is the primary form generated from FL-PIDD1.[18][19]

### Role of chaperones

The autoprocessing of PIDD1 rate to induce the precise conformational state necessary for efficient self-cleavage. [Hsp90](/source/Hsp90) directly associates with full-length PIDD1 (FL-PIDD1), subsequently recruiting [p23](/source/PTGES3) to facilitate the stabilization and folding of PIDD1 into its active configuration.[20] [Hsp70](/source/Hsp70), another key [chaperone](/source/Chaperone_(protein)), binds not only to full-length PIDD1 (FL-PIDD1) but also to its cleavage fragments, PIDD-N and PIDD-C, although the specific role of this interaction is not yet fully understood. In addition to facilitating autoprocessing, [Hsp90](/source/Hsp90) plays a crucial role in maintaining PIDD1's stability and function, highlighting the importance of [chaperones](/source/Chaperone_(protein)) in controlling both PIDD1 self-cleavage and its overall [protein](/source/Protein) levels. When [Hsp90](/source/Hsp90) is inhibited, PIDD1 undergoes rapid degradation through the E3 ubiquitin-protein ligase [CHIP](/source/STUB1) (also called STUB1), which appears to favor the [ubiquitination](/source/Ubiquitination) of PIDD-C over PIDD-CC. [CHIP](/source/STUB1) directly interacts with both PIDD1 and [Hsp70](/source/Hsp70), suggesting that [Hsp70](/source/Hsp70) may also be involved in regulating PIDD1. Although the PIDDosome can form in vitro after temperature changes, and the dissociation of [Hsp90](/source/Hsp90) is required for this process, [Hsp90s](/source/Hsp90) initial interaction is critical for PIDD1’s function. Interruption of the Hsp90-PIDD1 complex disrupts PIDD1 autoprocessing and its interactions with effector [proteins](/source/Proteins).[21]

## Multiprotein Complexes Containing PIDD1

### PIDDosome

PIDD-CC serves as a nucleating agent for the assembly of a complex with the dual adaptor [protein](/source/Protein) RAIDD, which plays a pivotal role in the recruitment and activation of [CASP2](/source/CASP2), potentially triggering apoptotic pathways. This assembly is widely recognized as the PIDDosome. In contrast, signaling pathways involving PIDD-C are primarily linked to the activation of [NF-κB](/source/NF-%CE%BAB), thereby enhancing cell survival. In response to [DNA damage](/source/DNA_damage), PIDD-C undergoes translocation to the [nucleus](/source/Cell_nucleus), where it forms a complex with [RIP1](/source/RIP1) and the [NF-κB](/source/NF-%CE%BAB) essential modulator (NEMO, also known as IKBKG), collectively termed the NEMO-PIDDosome.[22] The term "PIDDosome" is commonly used to refer to a multiprotein complex that is made up of [p53](/source/P53)-induced death domain protein 1 (PIDD1), the bipartite linker protein [CRADD](/source/CRADD) (also known as RAIDD), and the inactive precursor of the [caspase](/source/Caspase) family [endopeptidase](/source/Endopeptidase), called [caspase-2](/source/Caspase-2).[23]

### Caps-2-PIDDosome

Another important interaction is between [Caspase-2](/source/Caspase-2) enzyme and PIDD1 to form Caps-2-PIDDosome. The formation of the Caspase–2–PIDDosome relies on the interaction with the adaptor [protein](/source/Protein) RAIDD, which is characterized by the presence of a [death domain](/source/Death_domain) (DD) and a [caspase recruitment domain](/source/Caspase_recruitment_domain) (CARD).[24] RAIDD and PIDD-CC engage through their [death domains](/source/Death_domain) (DD) to form a high molecular weight complex. Additionally, the [N-terminal](/source/N-terminal) [caspase recruitment domain](/source/Caspase_recruitment_domain) (CARD) in RAIDD acts as a docking site for the [zymogen](/source/Zymogen) of [CASP2](/source/CASP2). This interaction is specifically associated with PIDD-CC, which is derived from the [human](/source/Human) PIDD1 transcript variant 1, since a small deletion in transcript variant 3 is likely sufficient to prevent RAIDD binding.[25][26] The presence of PIDD-C in the nucleus is vital for the activation of [NF-κB](/source/NF-%CE%BAB); however, PIDD-CC has also been detected in the [nucleolus](/source/Nucleolus), an [organelle](/source/Organelle) that serves various functions, including [ribosome biogenesis](/source/Ribosome_biogenesis) and [DNA repair](/source/DNA_repair).[27]

### PCNA-PIDDosome

In addition to the signaling pathways previously discussed, PIDD1 is essential for [translesion DNA synthesis](/source/Translesion_DNA_synthesis) (TLS), which allows for [DNA](/source/DNA) extension across damaged regions in response to [UV radiation](/source/UV_radiation). Within the nucleus, PIDD1 has been observed to associate with critical components of the replication machinery, such as [proliferating cell nuclear antigen](/source/Proliferating_cell_nuclear_antigen) (PCNA) and [replication factor C](/source/Replication_factor_C) subunits [RFC4](/source/RFC4) and [RFC5](/source/RFC5), forming a complex referred to as the PCNA-PIDDosome. These proteins were identified as interacting partners of overexpressed PIDD1 through [mass spectrometry](/source/Mass_spectrometry) analysis.[28] [PCNA](/source/PCNA) functions as a [DNA](/source/DNA)-sliding clamp that depends on [replication factor C](/source/Replication_factor_C) (RFC) for its correct positioning on [DNA](/source/DNA) and is crucial for loading [DNA polymerases](/source/DNA_polymerases) during the [replication](/source/DNA_replication) process. Additionally, [PCNA](/source/PCNA) is essential for various [DNA repair](/source/DNA_repair) activities. Importantly, the interactions among [8PIDD]]1, [PCNA](/source/PCNA), and [RFC5](/source/RFC5) are facilitated by their ZU5 domains. As a result, this complex can only form with full-length PIDD1 or, due to the limited availability of full-length PIDD1 and the preferential nuclear localization of its primary autoprocessing product, with PIDD-C.[29]

### Relation of PIDD1 to centrosomes

Recent investigations[which?] reveal that [CASP2](/source/CASP2) activation, which is dependent on PIDD1, does not lead to cell death or activate [p53](/source/P53) in reaction to [DNA damage](/source/DNA_damage) (such as that induced by doxorubicin) or during prolonged mitotic arrest (as observed with taxol treatment). In contrast, the [p53](/source/P53) activation linked to [centrosome](/source/Centrosome) amplification—a process that can occur following failed [cytokinesis](/source/Cytokinesis)—undoubtedly depends on the [Caspase-2](/source/Caspase-2)−PIDDosome complex.[30] Notably, PIDD1 appears to be integral in assessing the quantity of mature mother [centrioles](/source/Centrioles), utilizing a mechanism that has yet to be fully clarified. Furthermore, PIDD1 is situated at the distal ends of mature [centrosomes](/source/Centrosomes) within normal cells, suggesting its potential role in regulating centrosomal functions.[31] The assembly of the [Caspase-2](/source/Caspase-2)−PIDDosome can be triggered by the presence of multiple mature [centrioles](/source/Centrioles) with appendages. This activation leads to [CASP2](/source/CASP2)-mediated cleavage of [MDM2](/source/MDM2), resulting in the accumulation of [p53](/source/P53) and subsequent [cell cycle](/source/Cell_cycle) arrest mediated by [p21](/source/P21). Notably, these processes occur without causing significant [cell death](/source/Cell_death). Similarly, the depletion of [centrosomes](/source/Centrosomes) undermines the effectiveness of this pathway during instances of [cytokinesis](/source/Cytokinesis) failure. In contrast, overexpressing [polo-like kinase 4](/source/Polo-like_kinase_4) (PLK4), which promotes the formation of additional [centrosomes](/source/Centrosomes), is sufficient to activate the pathway even when [cytokinesis](/source/Cytokinesis) is not compromised.[32]

## Function

The protein encoded by this gene contains a [leucine-rich repeat](/source/Leucine-rich_repeat) and a [death domain](/source/Death_domain). This protein has been shown to interact with other [death domain](/source/Death_domain) proteins, such as Fas (TNFRSF6)-associated via death domain ([FADD](/source/FADD)) and [MAP-kinase](/source/Mitogen-activated_protein_kinase) activating death domain-containing protein (MADD), and thus may function as an adaptor protein in cell death-related signaling processes. The expression of the mouse counterpart of this gene has been found to be positively regulated by the tumor suppressor [p53](/source/P53) and to induce cell apoptosis in response to [DNA damage](/source/DNA_damage), which suggests a role for this gene as an effector of [p53](/source/P53)-dependent [apoptosis](/source/Apoptosis). Three alternatively spliced transcript variants encoding distinct isoforms have been reported.[1]

Besides its pro-apoptotic function it may also be involved in [DNA repair](/source/DNA_repair) as part of a protein complex formed together with the catalytic subunit of DNA-PK ([DNA-PKcs](/source/DNA-PKcs)) and [caspase 2](/source/Caspase_2). Signaling pathways involving PIDD-C have been associated with the activation of [NF-κB](/source/NF-%CE%BAB) and the promotion of [cell survival](/source/Cell_survival). Following [DNA damage](/source/DNA_damage), PIDD-C relocates to the nucleus, where it forms a complex with [RIP1](/source/RIP1) and the [NF-kappa-B](/source/NF-kappa-B) inhibitor kinase subunit gamma (NEMO, or IKBKG), collectively referred to as the '[NEMO](/source/IKBKG)-PIDDosome.'[33][34]

PIDD1 is also essential for [translesion DNA synthesis](/source/Translesion_DNA_synthesis) (TLS), which enables [DNA](/source/DNA) elongation across lesions in response to UV exposure. Inside the nucleus, PIDD1 forms a complex with critical replication machinery components, including [proliferating cell nuclear antigen](/source/Proliferating_cell_nuclear_antigen) (PCNA), [replication factor C](/source/Replication_factor_C) subunit 5 (RFC5), and RFC4, known collectively as the [PCNA](/source/PCNA)-PIDDosome. These proteins were identified as binding partners of overexpressed PIDD1 through [mass spectrometry](/source/Mass_spectrometry) analysis. [PCNA](/source/PCNA) functions as a [DNA](/source/DNA) sliding clamp that requires [RFC](/source/Replication_factor_C) for its correct placement on the DNA and is crucial for loading [DNA polymerases](/source/DNA_polymerases) during the replication process.[35]

Moreover, the activation of [p53](/source/P53), which occurs in response to centrosome amplification—commonly resulting from failed [cytokinesis](/source/Cytokinesis)—clearly relies on the [Caspase-2](/source/Caspase-2)−PIDDosome. Notably, PIDD1 seems to check the number of mature mother [centrioles](/source/Centrioles), though the specific mechanism by which it does so remains to be understood. Additionally, PIDD1 localizes to the distal end of mature [centrosomes](/source/Centrosomes) in healthy cells, indicating a possible role in [centrosome](/source/Centrosome) function or stability.[36]

## Caspase-2-PIDDosome

[Caspases](/source/Caspase) are a family of [cysteine proteases](/source/Cysteine_proteases) that play key roles in regulating [apoptosis](/source/Apoptosis) and inflammatory responses. These enzymes are divided into two main groups: initiator and executioner [caspases](/source/Caspase), based on their structure and function. Initiator [caspases](/source/Caspase), such as [caspase-8](/source/Caspase-8) and [caspase-9](/source/Caspase-9), become activated through the formation of large protein complexes, which promote dimerization and self-cleavage. Once activated, they initiate the activation of [effector caspases](/source/Effector_caspase), like [caspase-3](/source/Caspase-3) and [caspase-7](/source/Caspase-7), which then execute the final stages of [programmed cell death](/source/Programmed_cell_death).[37] [Caspase-2](/source/Caspase-2) has similar structure to the initiator [caspase-9](/source/Caspase-9), particularly due to the presence of a [caspase activation and recruitment domain](/source/Caspase_activation_and_recruitment_domain) (CARD). Its activation mechanism also involves dimerization, followed by autoprocessing, which is essential for its full activation.[38] Similar to [caspase-9](/source/Caspase-9) and its role within the [apoptosome](/source/Apoptosome), the multiprotein complex that facilitates [caspase-2](/source/Caspase-2) activation has been designated as the "PIDDosome" ([Caspase-2](/source/Caspase-2)-PIDDosome). This structure is formed by the C-terminal fragment of PIDD1 (p53-induced death domain protein 1) and RAIDD (receptor-interacting protein-associated ICH-1/CED-3 homolog with a [death domain](/source/Death_domain), also known as [CRADD](/source/CRADD)) in a 5:5 stoichiometric ratio. Two additional RAIDD molecules are positioned on top of the core complex, completing its assembly.[39][40] RAIDD functions as a dual adaptor protein, featuring specialized domains that facilitate key interactions. The C-terminal [death domain](/source/Death_domain) (DD) of RAIDD interacts with the corresponding DD of PIDD1, while the N-terminal region contains a [caspase activation and recruitment domain](/source/Caspase_activation_and_recruitment_domain) (CARD) that promotes homotypic binding with procaspase-2. This configuration enables RAIDD to play a critical role in the signaling pathways that lead to [apoptosis](/source/Apoptosis).[41][42] The binding of procaspase-2 to the complex positions the [caspase-2](/source/Caspase-2) monomers in close proximity, which promotes their dimerization and initiates autocatalytic cleavage, resulting in activation.[43] In addition to [DNA damage](/source/DNA_damage), several other factors have been identified as potential triggers for [caspase-2](/source/Caspase-2) activation, both within and outside the PIDDosome. These activation signals are varied and encompass conditions such as heat shock, alterations to the cytoskeleton, and the buildup of β-amyloids.[44][45][46] Importantly, caspase-2 and the PIDDosome play essential role in "polyploidy checkpoint."[47] Importantly, [caspase-2](/source/Caspase-2) and the PIDDosome play essential role in "polyploidy checkpoint." Triggered by the presence of extra [centrosomes](/source/Centrosomes) (supernumeray centrosomes), which often occur following unsuccessful [cell division](/source/Cell_division) (cytokinesis), the PIDDosome activates [caspase-2](/source/Caspase-2). This activation leads to the proteolytic inactivation of [MDM2](/source/MDM2), resulting in the activation of a [p53](/source/P53) response. Additionally, recent research has connected [caspase-2](/source/Caspase-2) to the monitoring of [aneuploidy](/source/Aneuploidy) in [cancer](/source/Cancer), although the exact mechanisms involved are not yet clearly defined.[48][49][50]

## PIDD1 and Cancer

Tumor protein [p53](/source/P53) (TP53, often referred to as p53) regulates a sophisticated network of tumor-suppressive responses to prevent the growth and persistence of cells with extra [centrosomes](/source/Centrosomes). These responses include halting [cell division](/source/Cell_division), promoting [cellular senescence](/source/Cellular_senescence), initiating controlled [cell death](/source/Cell_death), and, in instances of [whole-genome duplication](/source/Whole-genome_duplication), activating [immune surveillance](/source/Immune_surveillance) by [cytotoxic T cells](/source/Cytotoxic_T_cells).[51] [CASP2](/source/CASP2) plays a very important role in regulation and activation of [p53](/source/P53) in response to extra [centrosomes](/source/Centrosomes). Its activation is dependent on the formation of the "PIDDosome," a large protein complex that includes p53-induced death domain protein 1 (PIDD1), [CASP2](/source/CASP2), and [RIPK1]] containing a death domain (CRADD, commonly referred to as RAIDD). This complex enables [CASP2](/source/CASP2) to inactivate [MDM2](/source/MDM2), a key inhibitor of [p53](/source/P53), thereby promoting the activation of [p53](/source/P53).[52] In a study, Evans and colleagues conducted a genome-wide [CRISPR-Cas9](/source/CRISPR-Cas9) knockout screen using immortalized retinal pigment epithelial cells (hTERT RPE-1), modified to overexpress PLK4, which induces [centriole](/source/Centriole) overduplication. The cells also had constant depletion of ubiquitin-specific peptidase 28 (USP28) and tripartite motif-containing 37 (TRIM37), in order to suppress pathways typically activated by [centrosome](/source/Centrosome) loss. This screening identified 30 genes involved in halting the proliferation of hTERT RPE-1 cells with excess [centrosomes](/source/Centrosomes) (supetnumerary centrosomes), with 23 of these genes previously linked to [centrosome](/source/Centrosome)-related functions.[53] These genes encode a variety of well established PIDDosome components and significant signaling proteins, including PIDD1, [CRADD](/source/CRADD), [CASP2](/source/CASP2), [p53](/source/P53), and cyclin-dependent kinase inhibitor 1A (CDKN1A, often referred to as p21). They also encompass four proteins not previously associated with PIDDosome signaling: centrosomal protein 20 (CEP20, also known as FOPNL), C2 domain-containing protein 3 (C2CD3), which is involved in [centriole](/source/Centriole) elongation, sodium channel and clathrin linker 1 (SCLT1), and ankyrin repeat domain 26 (ANKRD26). The ability of these proteins to inhibit the proliferation of cells overexpressing PLK4 was confirmed through competition assays, underscoring their important functions in [cell cycle](/source/Cell_cycle) regulation.[54] Inadequate [centrosome](/source/Centrosome) clustering resulted in a reduced activation of the PIDDosome, as shown by diminished [CASP2](/source/CASP2) activation and lower [p21](/source/P21) levels in RPE-1 cells with PLK4 overexpression and absent ANKRD26. Further experiments, involving both ANKRD26-competent and -deficient RPE-1 cells along with various full-length proteins, mutants lacking specific domains, and non-cleavable variants, demonstrated that PIDD1's recruitment to [centrioles](/source/Centriole) is mediated by the interaction between the acidic region of ANKRD26 and the UPA domain of the C-terminal part of PIDD1 (PIDD1-CC), which arises from PIDD1's autoproteolytic processing. Importantly, in the context of inducible PLK4, this interaction was critical for the activation of the PIDDosome and the resulting cell cycle arrest. Furthermore, a study examining 20 different human tumors uncovered a recurrent mutation in ANKRD26 that adversely affects the interaction between ANKRD26 and PIDD1 with centrosomes, thereby increasing the survival of cells with more than required number of [centrosomes](/source/Centrosome).[55] The process of [centrosome](/source/Centrosome) accumulation initiates a signaling pathway characterized by the involvement of [Caspase-2](/source/Caspase-2) and the PIDDosome, which collectively contribute to the stabilization of [p53](/source/P53) and the induction of [p21](/source/P21) expression. This series of events can lead to an increase in PIDD1 levels over time, as it is also a downstream target of [p53](/source/P53). The observed rise in PIDD1 expression is likely a result of subsequent [DNA damage](/source/DNA_damage) occurring in cells that fail to effectively arrest their [cell cycle](/source/Cell_cycle) in the presence of excess [centrosomes](/source/Centrosome). Consequently, this situation may activate [p53](/source/P53) through either the conventional [DNA damage](/source/DNA_damage) response mechanism or as a result of delayed M-phase progression caused by complications in [chromosome](/source/Chromosome) alignment.[56] This mechanism guarantees the effective operation of the [p21](/source/P21) checkpoint, which, in turn, promotes the viability of aneuploid cells. At the same time, a lack of [CASP2](/source/CASP2) intensifies tumor advancement in this cancer model following treatment with cisplatin, leading to an accelerated progression of the malignancy.[57] PIDDosome-deficient animals provide an intriguing model for exploring the effects of ploidy on liver function and regenerative processes, avoiding the complications that arise from a global deficiency of [p53](/source/P53). It is noteworthy that several cell types become [polyploid](/source/Polyploid) during organ development or in response to infections. For example, cardiomyocytes enhance their ploidy during terminal differentiation, while viral infections can induce cell fusion, and bacterial infections may lead to the formation of multinucleated giant cells in macrophages.[58] Reflecting on the previous discussions, it is plausible to propose that PIDD1 might be activated in certain circumstances, which positions it as a promising candidate for pharmacological strategies aimed at influencing these processes.

### Recent Interests on PIDD1

Over the past few years, biallelic pathogenic variants in the CRADD gene have been strongly associated with a rare neurodevelopmental disorder (MRT34; MIM 614499), known as the "thin" lissencephaly (TLIS) variant. This disorder is characterized by pachygyria, primarily affecting the anterior regions of the brain, and is accompanied by megalencephaly, epilepsy, and intellectual disability (ID).[2] This discovery has drawn increased attention to the PIDDosome complex, revealing a wider array of biological functions beyond its conventional role in apoptosis triggered by DNA damage.[3] In this regard, PIDD1, a CRADD-interacting protein, functions as a sensor that monitors centrosome numbers and plays a vital role in controlling cellular differentiation during key processes such as organogenesis and tissue regeneration.[4][5] Recently, four homozygous variants in the PIDD1 gene have been identified among 11 individuals from five separate families, all of whom present with nonsyndromic intellectual disability. Nevertheless, comprehensive clinical and neuroimaging data for these cases are limited.[6]

## References

1. ["Entrez Gene: LRDD leucine-rich repeats and death domain containing"](https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55367)

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## Further reading

- Telliez JB, Bean KM, Lin LL (2000). "LRDD, a novel leucine rich repeat and death domain containing protein". *Biochim. Biophys. Acta*. **1478** (2): 280–8. [doi:10.1016/S0167-4838(00)00029-7](https://doi.org/10.1016/S0167-4838(00)00029-7). [PMID 10825539](https://pubmed.ncbi.nlm.nih.gov/10825539)
- Lin Y, Ma W, Benchimol S (2000). "Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis". *Nat. Genet.*. **26** (1): 122–7. [doi:10.1038/79102](https://doi.org/10.1038/79102). [PMID 10973264](https://pubmed.ncbi.nlm.nih.gov/10973264). [S2CID 10601123](https://api.semanticscholar.org/CorpusID:10601123)
- Strausberg RL, Feingold EA, Grouse LH, etal (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". *Proc. Natl. Acad. Sci. U.S.A.*. **99** (26): 16899–903. [Bibcode:2002PNAS...9916899M](https://ui.adsabs.harvard.edu/abs/2002PNAS...9916899M). [doi:10.1073/pnas.242603899](https://doi.org/10.1073/pnas.242603899). [PMC 139241](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139241). [PMID 12477932](https://pubmed.ncbi.nlm.nih.gov/12477932)
- Ota T, Suzuki Y, Nishikawa T, etal (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". *Nat. Genet.*. **36** (1): 40–5. [doi:10.1038/ng1285](https://doi.org/10.1038/ng1285). [PMID 14702039](https://pubmed.ncbi.nlm.nih.gov/14702039)
- Tinel A, Tschopp J (2004). "The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress". *Science*. **304** (5672): 843–6. [Bibcode:2004Sci...304..843T](https://ui.adsabs.harvard.edu/abs/2004Sci...304..843T). [doi:10.1126/science.1095432](https://doi.org/10.1126/science.1095432). [PMID 15073321](https://pubmed.ncbi.nlm.nih.gov/15073321). [S2CID 6583298](https://api.semanticscholar.org/CorpusID:6583298)
- Brandenberger R, Wei H, Zhang S, etal (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". *Nat. Biotechnol.*. **22** (6): 707–16. [doi:10.1038/nbt971](https://doi.org/10.1038/nbt971). [PMID 15146197](https://pubmed.ncbi.nlm.nih.gov/15146197). [S2CID 27764390](https://api.semanticscholar.org/CorpusID:27764390)
- Gerhard DS, Wagner L, Feingold EA, etal (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". *Genome Res.*. **14** (10B): 2121–7. [doi:10.1101/gr.2596504](https://doi.org/10.1101/gr.2596504). [PMC 528928](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC528928). [PMID 15489334](https://pubmed.ncbi.nlm.nih.gov/15489334)
- Rual JF, Venkatesan K, Hao T, etal (2005). "Towards a proteome-scale map of the human protein-protein interaction network". *Nature*. **437** (7062): 1173–8. [Bibcode:2005Natur.437.1173R](https://ui.adsabs.harvard.edu/abs/2005Natur.437.1173R). [doi:10.1038/nature04209](https://doi.org/10.1038/nature04209). [PMID 16189514](https://pubmed.ncbi.nlm.nih.gov/16189514). [S2CID 4427026](https://api.semanticscholar.org/CorpusID:4427026)
- Janssens S, Tinel A, Lippens S, Tschopp J (2006). "PIDD mediates NF-kappaB activation in response to DNA damage". *Cell*. **123** (6): 1079–92. [doi:10.1016/j.cell.2005.09.036](https://doi.org/10.1016/j.cell.2005.09.036). [PMID 16360037](https://pubmed.ncbi.nlm.nih.gov/16360037). [S2CID 15953086](https://api.semanticscholar.org/CorpusID:15953086)
- Vakifahmetoglu H, Olsson M, Orrenius S, Zhivotovsky B (2006). "Functional connection between p53 and caspase-2 is essential for apoptosis induced by DNA damage". *Oncogene*. **25** (41): 5683–92. [doi:10.1038/sj.onc.1209569](https://doi.org/10.1038/sj.onc.1209569). [PMID 16652156](https://pubmed.ncbi.nlm.nih.gov/16652156)
- Pick R, Badura S, Bösser S, Zörnig M (2006). "Upon intracellular processing, the C-terminal death domain-containing fragment of the p53-inducible PIDD/LRDD protein translocates to the nucleoli and interacts with nucleolin". *Biochem. Biophys. Res. Commun.*. **349** (4): 1329–38. [doi:10.1016/j.bbrc.2006.08.176](https://doi.org/10.1016/j.bbrc.2006.08.176). [PMID 16982033](https://pubmed.ncbi.nlm.nih.gov/16982033)
- Tinel A, Janssens S, Lippens S, etal (2007). "Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-κB pathway". *EMBO J.*. **26** (1): 197–208. [doi:10.1038/sj.emboj.7601473](https://doi.org/10.1038/sj.emboj.7601473). [PMC 1782377](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782377). [PMID 17159900](https://pubmed.ncbi.nlm.nih.gov/17159900)
- Park HH, Wu H (2007). "Crystallization and preliminary X-ray crystallographic studies of the oligomeric death-domain complex between PIDD and RAIDD". *Acta Crystallographica Section F*. **63** (Pt 3): 229–32. [doi:10.1107/S1744309107007889](https://doi.org/10.1107/S1744309107007889). [PMC 2330181](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330181). [PMID 17329820](https://pubmed.ncbi.nlm.nih.gov/17329820)
- Bradley G, Tremblay S, Irish J, etal (2007). "The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma". *Br. J. Cancer*. **96** (9): 1425–32. [doi:10.1038/sj.bjc.6603745](https://doi.org/10.1038/sj.bjc.6603745). [PMC 2360189](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360189). [PMID 17437012](https://pubmed.ncbi.nlm.nih.gov/17437012)

---
Adapted from the Wikipedia article [LRDD](https://en.wikipedia.org/wiki/LRDD) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/LRDD?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.