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- Title
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.
- Authors
Cicconi, Alessandro; Rai, Rekha; Xiong, Xuexue; Broton, Cayla; Al-Hiyasat, Amer; Hu, Chunyi; Dong, Siying; Sun, Wenqi; Garbarino, Jennifer; Bindra, Ranjit S.; Schildkraut, Carl; Chen, Yong; Chang, Sandy
- 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. Primary microcephaly is a clinical feature of several human telomere disorder syndromes. Here the authors reveal a role of Microcephalin 1 in promoting telomere replication and repair.
- Subjects
TELOMERES; DNA repair; DNA damage; CHROMOSOMES; CRYSTAL structure
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-19674-0