Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.
| Publication Type | Academic Article |
| Authors | Cicconi A, Rai R, Xiong X, Broton C, Al-Hiyasat A, Hu C, Dong S, Sun W, Garbarino J, Bindra R, Schildkraut C, Chen Y, Chang S |
| Journal | Nat Commun |
| Volume | 11 |
| Issue | 1 |
| Pagination | 5861 |
| Date Published | 11/17/2020 |
| ISSN | 2041-1723 |
| Keywords | Cell Cycle Proteins, Cytoskeletal Proteins, Microcephaly, Telomere, Telomeric Repeat Binding Protein 2 |
| 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. |
| DOI | 10.1038/s41467-020-19674-0 |
| PubMed ID | 33203878 |
| PubMed Central ID | PMC7672075 |