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Fanconi Anemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for FA include hereditary breast and ovarian cancer (heterozygous pathogenic variants in FANCD1/BRCA2, FANCJ/BRIP1, and FANCN/PALB2), pancreatic cancer (heterozygous pathogenic variants in FANCN/PALB2), xeroderma pigmentosum (FANCN), Cockayne syndrome (FANCN), XFE progeroid syndrome (FANCN), Bloom syndrome (spontaneous chromosome breakage independent of diepoxybutane), ataxia-telangiectasia (spontaneous chromosome breakage independent of diepoxybutane), Nijmegen breakage syndrome (NBS; short stature, progressive microcephaly with loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, and an increased risk for lymphoma; increased chromosome breakage with MMC; autosomal recessive disorder due to NBN pathogenic variants), Seckel syndrome (growth retardation, microcephaly with intellectual disability, characteristic “bird-headed” facial appearance, pancytopenia or AML, increased chromosome breakage with DNA crosslinking agents such as MMC and DEB, autosomal recessive disorder due to biallelic pathogenic variants in ATR, NIN, ATRIP, RBBP8, CEP152, CENPJ, and CEP63), neurofibromatosis type 1 (café-au-lait macules), TAR syndrome (thrombocytopenia with absent radii), dyskeratosis congenita, Diamond−Blackfan anemia, Shwachman−Diamond syndrome, severe congenital neutropenia, amegakaryocytic thrombocytopenia, Baller−Gerold syndrome, Rothmund−Thomson syndrome, Roberts syndrome, Warsaw breakage syndrome, DK-phocomelia, VACTERL hydrocephalus syndrome (radial ray defects), and Wiskott−Aldrich syndrome [1,2,28–30].
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
The human PLK4, mapped onto chromosome 4q27-28 [47] is comprised of 970 amino acids (aa) [48] with a molecular mass of 109 kDa [49]. PLK1, 2, 3, and 5 possess two distinct polo-boxes while PLK4 possess triple polo box architecture, making it the most structurally divergent member of the PLK family [17]. PLK4 possesses an N-terminal kinase domain, a conserved central region called cryptic polo-box (CPB) domain comprising of two tandem polo-boxes namely polo box-1 (PB1) and polo box-2 (PB2), a C-terminal polo-box domain named as polo box-3 (PB3) and two linker regions (L1 and L2). The CPB serves as a bridge between the kinase and PB domain (Figure 1). The polo boxes of PLK4 dictate kinase activity, localization, substrate specificity, regulatory pathway and are involved in protein interaction. The full PB1-PB2 cassette exhibits a winged architecture and plays roles in PLK4 oligomerization, CEP152 binding and robust centriole targeting. CEP152 acts as a molecular scaffold to facilitate interaction of PLK4 with various proteins required for centriole biogenesis. Furthermore, PB1-PB2 homodimerization aids in PLK4 trans-autophosphorylation, subsequent ubiquitination, and degradation by SCF/β-TRCP complex. This autoregulatory mechanism is crucial for maintaining centriole number and PLK4 stability. PB3 domain plays an essential role in stimulating PLK4 kinase activity by relieving the L1-induced autoinhibition [50]. Similar to PB1-PB2 cassette, PB3 domain mediates centriole localization, although weakly [51]. Additionally, STIL binding to PB3 domain, and its subsequent phosphorylation by PLK4 facilitated STIL/SAS-6 interaction essential for procentriole formation [52]. Equally important are the PLK4 linker regions comprising of L1 that acts as a cis-acting kinase activity inhibitor under non-phosphorylated state and L2 that affects PLK4 dimer stability when autophosphorylated [50].