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Table 1 Examples of centrosomal proteins that are mutated in human microcephalic or ciliopathy disorders, and have known functional roles in DDR or genome integrity

From: Ciliogenesis and the DNA damage response: a stressful relationship

Protein Protein function Associated disease/clinical features Possible role in the DDR?
CEP63 Promotes accurate duplication of centrioles and assembly/integrity of the mitotic spindle Seckel syndrome (SCKL6); microcephaly, short stature/dwarfism and delayed speech development A substrate of DDR kinases and over-expression can lead to supernumerary centrosomes and DNA damage. MRNA over-expression in a cohort of neuroblastomas was associated with MYCN amplification and poor patient prognosis
CEP152 Cooperates with Cep63 to promote accurate centriole duplication Primary microcephaly (MCPH9) and Seckel syndrome (SCKL5); microcephaly, moderate cognitive impairment and mild behavioural disorders Chromosomal defects observed in SCKL5 patients with potential heightened replicative stress and DNA damage, although this has not been extensively studied to date
CEP164 Localises to the basal body to promote ciliogenesis Nephronophthisis-related ciliopathies; retinal degeneration (including blindness) and seizures Is a substrate of DDR kinases, localises to nuclear foci in response DNA damage and facilitates cellular responses to UV irradiation
CEP290 Required for the integrity of many centriolar satellites, microtubule organisation and ciliogenesis Bardet–Biedl (BBS14), Joubert (JBTS5), Meckel (MKS4) and Senior–Løken syndrome (SLSN6) syndromes; clinical features include retinal and renal abnormalities, brain malformation, dysplastic kidneys and nephronophthisis, respectively No overt increased cancer risk associated with BBS14, JBTS5, MKS4 or SLSN6. Many identified frameshift mutations identified in various cancers, with a 10 % mutation frequency in endometrial cancers (TCGA)
MCPH1 Required for cell cycle checkpoints in response to DNA damage, and preventing chromosome condensation (PCC) Primary microcephaly; microcephaly, growth retardation/dwarfism, cognitive impairment, radiation sensitivity and PCC evident in patient cells Prevents genome instability by facilitating cell cycle checkpoints in response to DNA damage. Deleted in several cancers including breast and ovarian cancer (TCGA). Increased incidence of lymphomas in MCPH1−/- mouse models
NEK8 Promotes cell cycle progression from G2-M and ciliogenesis by regulating Cyclin A–CDK activity Nephronophthisis (NPHP9) and renal-hepatic-pancreatic dysplasia (RHPD2); dysplasia in the kidney as well as in the liver and pancreas Promotes ATR-mediated cellular responses to replication stress to prevent to accumulation of DNA damage. Over-expressed in some breast tumours
PCNT Microtubule organisation, accurate chromosome segregation and ciliogenesis Microcephalic osteodysplastic primordial dwarfism type II (MOPDII); microcephaly, short stature and bone abnormalities Facilitates cellular responses to DNA damage through interaction with the DDR effector kinase CHK1