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

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)