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

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.

Molecular Genetics of Microcephaly Primary Hereditary: An Overview

“…Microcephalin 1 acts as a transcriptional repressor of hTERT and interacts with the anaphase-promoting complex via Cdc27 linking transcription with cell cycle progression [ 43 , 45 , 47 ]. In addition, it interacts with histone H2AX and is involved in the DNA damage repair mechanisms acting as tumor suppressor [ 43 , 45 , 48 , 49 , 50 ]. In mice, knockout of Mcph1 leads to defects in chromosome condensation, deficiencies in DNA repair, spindle misorientation and, eventually, to a reduction of the brain size mimicking the human disease [ 51 ].…”

MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface

“…Binding of MCPH1’s C-terminal BRCT domains to phosphorylated histone H2AX ( Venkatesh and Suresh, 2014 ) is thought to play a part in the DNA damage response, while the premature chromosome condensation caused by mutations within its N-terminal BRCT has been attributed to this domain’s defective association with the SWI/SNF nucleosome remodelling complex and SET1 ( Leung et al, 2011 ). MCPH1 is also thought to bind DNA and has been proposed to function in telomere maintenance, centriole organisation and CHK1 activation ( Alderton et al, 2006 ; Chang et al, 2020 ; Cicconi et al, 2020 ; Gruber et al, 2011 ; Lin and Elledge, 2003 ). In contradiction to the finding that MCPH1 binds directly to condensin II, it is widely believed that the N-terminal ~200 residues of MCPH1 compete with condensin II for chromosomal binding ( Yamashita et al, 2011 ), in other words, MCPH1 has been proposed to occupy loci required for condensin II’s chromosomal activity.…”

Replication of the Mammalian Genome by Replisomes Specific for Euchromatin and Heterochromatin

“…Deficiencies in DONSON would be expected to adversely influence the response to replication stress in these areas of the genome. DONSON is a member of a group of replication associated proteins, mutations in which result in microcephaly and dwarfism ( Bicknell et al, 2011 ; Evrony et al, 2017 ; Reynolds et al, 2017 ; Van Esch et al, 2019 ; Cicconi et al, 2020 ; Matos-Rodrigues et al, 2020 ; Starokadomskyy et al, 2021 ). Compromised replication through genomic areas with active transcription could have a negative impact on completing S phase and consequently, cell number, resulting in smaller brain and body size.…”