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

Caser Tena, Teresa, Maerz, Lars, Szafranski, Karol, Groth, Marco, Blatte, Tamara, Donow, Cornelia, Matysik, Sabrina, Walther, Paul, Jeggo, Penelope A, Burkhalter, Martin and Philipp, Melanie (2018) Resting cells rely on the DNA helicase component MCM2 to build cilia. Nucleic Acids Research. ISSN 0305-1048

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Q Science > QH Natural history > QH0301 Biology
Depositing User: Penny Jeggo
Date Deposited: 19 Oct 2018 13:30
Last Modified: 19 Oct 2018 14:19
URI: http://srodev.sussex.ac.uk/id/eprint/41738

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Project NameSussex Project NumberFunderFunder Ref
DNA damage responses in mammalian cells and their contribution to human health disorders; the end-stageG0217MRC-MEDICAL RESEARCH COUNCILG1000050