Skip to main content

Table 2 Examples of established DDR-associated proteins currently linked to ciliogenesis and/or ciliopathy disorders

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

Protein Protein function in DDR Role in ciliogenesis Associated human disease
ATMIN Co-factor of the PIKK ATM that promotes its activation and cellular responses to DNA damage and replication stress. Originally designated ASCIZ for ATM/ATR-substrate Chk2-interacting Zn(2 +)-finger protein Through its role as a transcription factor, it regulates WNT signalling that is important for correct morphogenesis of the developing lung and kidney of mice None associated to date, although recessive homozygous mutations in its binding partner ATM lead to the developmental and cancer predisposition syndrome Ataxia-telangiectasia
(A-T)
ATR Phosphoinositide 3-kinase related kinase (PIKK) central to co-ordinating cellular responses to replication stress by activating appropriate cell cycle checkpoints and homologous recombination mediated DNA repair processes Localises to the basal body in the developing eye of mice where it promotes ciliogenesis. Zebrafish genetic models of Seckel syndrome exhibit impair sonic hedgehog signalling and ciliogenesis Splicing defects and compound heterozygous mutations in ATR are causal for the growth retardation disease Seckel syndrome. ATR is therefore also known as SCKL1
FAN1 Structure-specific nuclease involved in the repair of DNA interstrand cross-links. Associated with the Fanconi Anaemia DNA repair pathway None presently known Biallelic mutations in FAN1 are causal for a subset karyomegalic interstitial nephritis and germ-line mutations in humans associated with colorectal cancer
MRE11 Key nuclease involved in resection of DNA double-strand breaks to promote their repair; mainly through homologous recombination processes None presently known Mutations in MRE11 are causal for the rare cancer-predisposition disease ataxia-telangiectasia-like disorder-1 (ATLD1). Homozygous recessive mutations are causal for a subset of nephronophthisis-related ciliopathies. Often over-expressed in cancers, and may promote increased error prone micro-homology end-joining DNA repair process that gives rise to genome instability
ORC1 Forms part of the origin recognition complex that initiates DNA replication. Also localises to the centrosome to regulate centrosome duplication and ciliogenesis Meier–Gorlin syndrome (MGS1); microcephaly, short stature/dwarfism and skeletal abnormalities. Note that mutations in related DNA replication proteins ORC4, ORC6, CDT1 and CDC6 all cause Meier–Gorlin syndrome Controls DNA replication, which is responsive to DNA damage through DDR signalling. Oncogene-induced replication stress can be a source of tumourigenic mutations, although it is not clear if reduced ORC1 function could facilitate this process
VCP/p97 Recruited to DNA breaks where it facilitates the recruitment of other DDR factors and their ubiquitylation-mediated regulation. Also involved in cellular responses to replication stress Recently shown to regulate the E3 ligase-mediated ubiquitylation of UBXN10 to control the trafficking rates of cilia by the intraflagellar transport B complex Mutations in VCP/p97 have been implicated as causal for inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD)