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

Nat Commun. 2020 Nov 17;11(1):5861. doi: 10.1038/s41467-020-19674-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism
  • Animals
  • Binding Sites
  • Calorimetry
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • DNA Damage
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Fibroblasts
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mice
  • Microcephaly / genetics*
  • Mutation
  • Protein Interaction Domains and Motifs
  • Serine Proteases / genetics
  • Serine Proteases / metabolism
  • Telomere / genetics*
  • Telomere / metabolism
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2 / chemistry
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism*

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • H2AX protein, mouse
  • Histones
  • MCPH1 protein, human
  • POT1 protein, human
  • TERF2 protein, human
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1