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 |