7c5d | pdb_00007c5d
Crystal structure of TRF2 TRFH domain in complex with a MCPH1 peptide
Structural highlights
FunctionTERF2_HUMAN Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3' single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.[1] [2] [3] Publication Abstract from PubMedTelomeres 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 (330)YRLSP(334) 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. Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.,Cicconi A, Rai R, Xiong X, Broton C, Al-Hiyasat A, Hu C, Dong S, Sun W, Garbarino J, Bindra RS, Schildkraut C, Chen Y, Chang S Nat Commun. 2020 Nov 17;11(1):5861. doi: 10.1038/s41467-020-19674-0. PMID:33203878[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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