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Resting cells rely on the DNA helicase component MCM2 to build cilia
journal contribution
posted on 2023-06-08, 12:55 authored by Teresa Caser Tena, Lars Maerz, Karol Szafranski, Marco Groth, Tamara Blatte, Cornelia Donow, Sabrina Matysik, Paul Walther, Penny Jeggo, Martin Burkhalter, Melanie PhilippMinichromosome maintenance (MCM) proteins facilitate replication by licensing origins and unwinding the DNA double strand. Interestingly, the number of MCM hexamers greatly exceeds the number of firing origins suggesting additional roles of MCMs. Here we show a hitherto unanticipated function of MCM2 in cilia formation in human cells and zebrafish that is uncoupled from replication. Zebrafish depleted of MCM2 develop ciliopathy-phenotypes including microcephaly and aberrant heart looping due to malformed cilia. In non-cycling human fibroblasts, loss of MCM2 promotes transcription of a subset of genes, which cause cilia shortening and centriole overduplication. Chromatin immunoprecipitation experiments show that MCM2 binds to transcription start sites of cilia inhibiting genes. We propose that such binding may block RNA polymerase II-mediated transcription. Depletion of a second MCM (MCM7), which functions in complex with MCM2 during its canonical functions, reveals an overlapping cilia-deficiency phenotype likely unconnected to replication, although MCM7 appears to regulate a distinct subset of genes and pathways. Our data suggests that MCM2 and 7 exert a role in ciliogenesis in post-mitotic tissues.
Funding
DNA damage responses in mammalian cells and their contribution to human health disorders; the end-stage; G0217; MRC-MEDICAL RESEARCH COUNCIL; G1000050
History
Publication status
- Published
File Version
- Published version
Journal
Nucleic Acids ResearchISSN
0305-1048Publisher
Oxford University PressExternal DOI
Issue
1Volume
47Page range
134-151Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-10-19First Open Access (FOA) Date
2018-10-19First Compliant Deposit (FCD) Date
2018-10-19Usage metrics
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