7C5D

Crystal structure of TRF2 TRFH domain in complex with a MCPH1 peptide

Summary for 7C5D

• Entry DOI: 10.2210/pdb7c5d/pdb
• Descriptor: Telomeric repeat-binding factor 2, Microcephalin, GLYCEROL, ... (4 entities in total)
• Functional Keywords: telomere, shelterin complex, trf2, mcph1, dna repair, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 52492.76

Authors

Xiong, X.,Chen, Y. (deposition date: 2020-05-19, release date: 2020-10-21, Last modification date: 2023-11-29)

Primary citation

Cicconi, A.,Rai, R.,Xiong, X.,Broton, C.,Al-Hiyasat, A.,Hu, C.,Dong, S.,Sun, W.,Garbarino, J.,Bindra, R.S.,Schildkraut, C.,Chen, Y.,Chang, S.
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.
Nat Commun, 11:5861-5861, 2020

PubMed 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 YRLSP 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.

PubMed: 33203878
DOI: 10.1038/s41467-020-19674-0

Experimental method

X-RAY DIFFRACTION (2.151 Å)