Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

Alessandro Cicconi, Rekha Rai, Xuexue Xiong, Cayla Broton, Amer Al-Hiyasat, Chunyi Hu, Siying Dong, Wenqi Sun, Jennifer Garbarino, Ranjit S. Bindra, Carl Schildkraut, Yong Chen () and Sandy Chang ()
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Alessandro Cicconi: Yale University School of Medicine
Rekha Rai: Yale University School of Medicine
Xuexue Xiong: State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Cayla Broton: Yale University School of Medicine
Amer Al-Hiyasat: Yale University School of Medicine
Chunyi Hu: State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Siying Dong: State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Wenqi Sun: State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Jennifer Garbarino: Yale University School of Medicine
Ranjit S. Bindra: Yale University School of Medicine
Carl Schildkraut: Albert Einstein College of Medicine
Yong Chen: State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Sandy Chang: Yale University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

Date: 2020
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DOI: 10.1038/s41467-020-19674-0

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