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Resting cells rely on the DNA helicase component MCM2 to build cilia

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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 Philipp
Minichromosome 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 Research

ISSN

0305-1048

Publisher

Oxford University Press

Issue

1

Volume

47

Page range

134-151

Department 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

2018-10-19

First Open Access (FOA) Date

2018-10-19

First Compliant Deposit (FCD) Date

2018-10-19

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